Image-guided, Robotically Delivered Transcranial Magnetic Stimulation Treatment for Combat-Related Post-Traumatic Stress Disorder

Not Applicable

Completed

Conditions: Stress Disorders, Post-Traumatic

Interventions: Device: Active repetitive transcranial magnetic stimulation
Device: robotic arm
Device: Sham repetitive transcranial magnetic stimulation

Registration Number: NCT02853032

Lead Sponsor: The University of Texas Health Science Center at San Antonio

Brief Summary: Mounting amounts of evidence suggests that non-invasive stimulation of the dorsolateral prefrontal cortex (DLPFC) using repetitive transcranial magnetic stimulation (rTMS) maybe a safe and effective treatment modality for Post-Traumatic Stress Disorder (PTSD). However the large variability in the magnitude of clinical outcomes reported is likely related to the current lack of knowledge of ideal side of stimulation (left vs right) and the limited precision in the targeting of brain circuits needed to obtain an optimal treatment response. In this protocol the investigators will: 1) generate individualized treatment plans based on an individual's functional Magnetic Resonance Imaging (fMRI) and meta-analytical based connectivity analysis to guide the delivery of adjunct, imaging-based \& robotically delivered rTMS to active duty military (ADM) subjects with PTSD participating in an intensive program providing integrated evidence-based psychotherapy and pharmacological management (Treatment as Usual (TAU)). 2) To use clinician ratings and self-report PTSD symptom scales, as well as other indicators of clinical change, to determine whether compared with TAU, addition of adjunct rTMS improves clinical outcomes. 3) To conduct neuroimaging-based assessments aimed to measure rTMS effects on network connectivity in ADM receiving treatment for PTSD and the potential correlation of connectivity changes with clinical outcomes.

Detailed Description: The investigators propose a randomized, double-blind, sham-controlled, 20 consecutive day trial of adjunct rTMS to the right DLPFC for ADM with PTSD receiving TAU at Laurel Ridge Treatment Center (LRTC; San Antonio, TX). Methods: Consenting ADM receiving TAU for PTSD at LRTC will be randomized to receive 20 consecutive days of adjunct rTMS according to one of these two treatment arms: Arm 1 TAU plus rTMS to the right DLPFC and Arm 2 TAU plus sham rTMS. At UTHSCSA's Research Imaging Institute (RII), where all brain imaging will be conducted, rTMS treatment plans will be generated based on (pre-treatment) anatomical and functional magnetic resonance imaging (fMRI) to guide the optimal robotic positioning of the TMS coil to accurately target each subject's DLPFC. Initial diagnostic interview and weekly clinical follows ups will be conducted at the LRTC by research clinicians blinded to subjects' research group. A comparison of baseline brain connectivity measurements with subjects' neuroimaging follow ups conducted at treatment Week 3 will be conducted to identify network connectivity changes potentially associated to treatment response.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 119

Inclusion Criteria

Male or female English-speaking active duty or recently retired veteran patients who have deployed post 9/11 receiving treatment at LRTC between the ages of 18-65 years;
Patients must have a diagnosis of PTSD confirmed by the Clinician-Administered PTSD Scale (CAPS-5) at screening,
Subjects must have a minimum PTSD Symptom Checklist (PCL-5) for DSM-V symptom severity rating of 25.

Exclusion Criteria

Subjects with a diagnostic history of bipolar disorder, schizophrenia or schizoaffective disorder as documented in the medical record.
Substance use disorder during the 12 months prior to screening; except that Mild - Moderate, but not Severe, Alcohol Use Disorder (using DSM-5 criteria) will be allowed as determined by LRTC medical provider review.
Any history or signs of serious medical or neurological illness including seizure disorders. Except for seizures, a subject with a clinical abnormality may be included only if the study clinician considers the illness will not introduce additional risk and will not interfere with the study procedures. This will be determined during the screening phase via self-report and/or medical history review.
History of traumatic brain injury (TBI) with loss of consciousness for 20 minutes or more as determined by the History of Head Injuries questionnaire.
Females will be excluded if they are pregnant (i.e. positive pregnancy test identified after their LRTC intake).
Any history or signs of metal objects deemed unsafe for MRI or that may adversely affect image quality of the brain region (e.g. surgical clips, cardiac pacemakers, metal implants, etc.) in the body at the time of screening as indicated by self-report. MRI can have risks for persons with foreign bodies implanted in their body.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active rTMS to the right DLPFC	robotic arm	Active repetitive transcranial magnetic stimulation will be delivered to the right DLPFC using connectivity-based, image-guided aiming with the rTMS coil positioned using a robotic arm. In this arm, active rTMS will be delivered at 20 Hertz (Hz) in 2 sec trains with 14 sec inter-train intervals, 20 minutes/session (i.e. 1,600 pulses/session), 7 days/week for 20 consecutive days.
Active rTMS to the right DLPFC	Active repetitive transcranial magnetic stimulation	Active repetitive transcranial magnetic stimulation will be delivered to the right DLPFC using connectivity-based, image-guided aiming with the rTMS coil positioned using a robotic arm. In this arm, active rTMS will be delivered at 20 Hertz (Hz) in 2 sec trains with 14 sec inter-train intervals, 20 minutes/session (i.e. 1,600 pulses/session), 7 days/week for 20 consecutive days.
Sham rTMS to the right DLPFC	Sham repetitive transcranial magnetic stimulation	Sham repetitive transcranial magnetic stimulation will be delivered to the right DLPFC using connectivity-based, image-guided aiming with the rTMS coil positioned using a robotic arm. In this arm, sham rTMS will be delivered at 20 Hz in 2 sec trains with 14 sec inter-train intervals, 20 minutes/session (i.e. 1,600 pulses/session), 7 days/week for 20 consecutive days.
Sham rTMS to the right DLPFC	robotic arm	Sham repetitive transcranial magnetic stimulation will be delivered to the right DLPFC using connectivity-based, image-guided aiming with the rTMS coil positioned using a robotic arm. In this arm, sham rTMS will be delivered at 20 Hz in 2 sec trains with 14 sec inter-train intervals, 20 minutes/session (i.e. 1,600 pulses/session), 7 days/week for 20 consecutive days.

Primary Outcome Measures

Name	Time	Method
Change in PTSD Severity as Measured by the PTSD Checklist (PCL-5)	Baseline to three weeks (the conclusion of rTMS treatment)	The PCL-5 is a 20-item measure that assesses the presence and severity of PTSD symptoms. Responders are asked to rate how bothered they have been by each item in the past month on a 5-point Likert scale ranging from 0-4. Items are summed to provide a total score. Severity can be determined adding scores of each item together to determine a total score. The range is 0-80, with a lower score suggesting a lower incidence of PTSD. A total score of 33 or higher suggests the patient needs further assessment to confirm a diagnosis of PTSD.

Secondary Outcome Measures

Name	Time	Method
Remission From Depression as Measured by the Montgomery-Ashberg Depression Rating Scale (MADRS)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Each item yields a score of 0 to 6 and the overall score ranges from 0 to 60. Higher scores indicate increasing depressive symptoms. Cut-off points include: 0 to 6 - symptom absent, 7 to 19 - mild depression, 30 to 34 - moderate, 35 to 60 - severe depression. Remission from depression is defined as a MADRS score less than or equal to 10.
Clinically Significant Response as Measured by the PTSD Checklist for DSM-5 (PCL-5)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The PCL-5 is a 20-item measure that assesses the presence and severity of PTSD symptoms. Responders are asked to rate how bothered they have been by each item in the past month on a 5-point Likert scale ranging from 0-4. Items are summed to provide a total score. Severity can be determined adding scores of each item together to determine a total score. The range is 0-80, with a lower score suggesting a lower incidence of PTSD. A total score of 33 or higher suggests the patient needs further assessment to confirm a diagnosis of PTSD. A clinically significant response is defined as a 10-20 point decrease in the PCL-5 scores.
Remission From Depression as Measured by the 9-item Patient Health Questionnaire (PHQ-9)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The PHQ-9 is a brief, 9-item scale that includes only the depression-related items from the PHQ. The PHQ-9 has been validated for use in primary care settings and can be used to make a tentative diagnosis of depression and to monitor depression severity and response to treatment in the past 2 weeks. Higher scores indicate increasing depressive symptoms. Depression Severity: 0-4 none, 5-9 mild, 10-14 moderate, 15-19 moderately severe, 20-27 severe. Remission from severe depression is defined as a PHQ-9 score less than or equal to 14.
Change in Depression Severity as Measured by the 9-item Patient Health Questionnaire (PHQ-9)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The PHQ-9 is a brief, 9-item scale that includes only the depression-related items from the PHQ. The PHQ-9 has been validated for use in primary care settings and can be used to make a tentative diagnosis of depression and to monitor depression severity and response to treatment in the past 2 weeks. Higher scores indicate increasing depressive symptoms. Depression Severity: 0-4 none, 5-9 mild, 10-14 moderate, 15-19 moderately severe, 20-27 severe. Remission from severe depression is defined as a PHQ-9 score less than or equal to 14.
Clinically Significant Response in Depression Severity as Measured by the Montgomery-Ashberg Depression Rating Scale (MADRS)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Each item yields a score of 0 to 6 and the overall score ranges from 0 to 60. Higher scores indicate increasing depressive symptoms. Cut-off points include: 0 to 6 - symptom absent, 7 to 19 - mild depression, 30 to 34 - moderate, 35 to 60 - severe depression. Clinically significant response is defined as greater than or equal to a 50% decrease in the MADRS score.
Remission From PTSD as Measured by the PTSD Checklist for DSM-5 (PCL-5)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The PCL-5 is a 20-item measure that assesses the presence and severity of PTSD symptoms. Responders are asked to rate how bothered they have been by each item in the past month on a 5-point Likert scale ranging from 0-4. Items are summed to provide a total score. Severity can be determined adding scores of each item together to determine a total score. The range is 0-80, with a lower score suggesting a lower incidence of PTSD. A total score of 33 or higher suggests the patient needs further assessment to confirm a diagnosis of PTSD. Remission is defined as a PCL-5 score less than or equal to 33.
Change in PTSD Severity as Measured by the PTSD Checklist for DSM-5 (PCL-5)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	PCL-5 is a 20-item measure that assesses the presence and severity of PTSD symptoms. Responders are asked to rate how bothered they have been by each item in the past month on a 5-point Likert scale ranging from 0-4. Items are summed to provide a total score. Severity can be determined adding scores of each item together to determine a total score. The range is 0-80, with a lower score suggesting a lower incidence of PTSD. A total score of 33 or higher suggests the patient needs further assessment to confirm a diagnosis of PTSD.
Change in PTSD Severity as Measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)	Baseline to seven weeks (four weeks after the conclusion of rTMS treatment)	The CAPS-5 is a 30-item structured interview that can be used to make current (past month) diagnosis of PTSD, make lifetime diagnosis of PTSD, and assess PTSD symptoms over the past week. The assessor combines information about frequency and intensity of an item into a single severity rating. CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms; the range of the scores is 0-80; with a higher score indicating a higher incidence of PTSD symptoms. To meet criteria for PTSD, a patient must have: 1. A traumatic event 2. At least one "Re-experiencing" symptom 3. At least one "Avoidance" symptom 4. At least two "Negative alterations in cognitions and mood" symptoms 5. At least two "Alterations in arousal and reactivity" symptoms 6. The trauma must last at least a month 7. The trauma must cause impairment
Change in PTSD Severity as Measured by the Clinician-Administered PTSD Scale (CAPS-5)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The CAPS-5 is a 30-item structured interview that can be used to make current (past month) diagnosis of PTSD, make lifetime diagnosis of PTSD, and assess PTSD symptoms over the past week. The assessor combines information about frequency and intensity of an item into a single severity rating. CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms; the range of the scores is 0-80; with a higher score indicating a higher incidence of PTSD symptoms. To meet criteria for PTSD, a patient must have: 1. A traumatic event 2. At least one "Re-experiencing" symptom 3. At least one "Avoidance" symptom 4. At least two "Negative alterations in cognitions and mood" symptoms 5. At least two "Alterations in arousal and reactivity" symptoms 6. The trauma must last at least a month 7. The trauma must cause impairment
Change in Depression Severity as Measured by the Montgomery-Ashberg Depression Rating Scale (MADRS)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Each item yields a score of 0 to 6 and the overall score ranges from 0 to 60. Higher scores indicate increasing depressive symptoms. Cut-off points include: 0 to 6 - symptom absent, 7 to 19 - mild depression, 30 to 34 - moderate, 35 to 60 - severe depression.
Clinically Significant Response in Depression Severity as Measured by the 9-item Patient Health Questionnaire (PHQ-9)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The PHQ-9 is a brief, 9-item scale that includes only the depression-related items from the PHQ. The PHQ-9 has been validated for use in primary care settings and can be used to make a tentative diagnosis of depression and to monitor depression severity and response to treatment in the past 2 weeks. Higher scores indicate increasing depressive symptoms. Depression Severity: 0-4 none, 5-9 mild, 10-14 moderate, 15-19 moderately severe, 20-27 severe. Remission from severe depression is defined as a PHQ-9 score less than or equal to 14.
Clinically Significant Response as Measured by the Clinician-Administered PTSD Scale (CAPS-5)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The CAPS-5 is a 30-item structured interview that can be used to make current (past month) diagnosis of PTSD, make lifetime diagnosis of PTSD, and assess PTSD symptoms over the past week. The assessor combines information about frequency and intensity of an item into a single severity rating. CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms; the range of the scores is 0-80; with a higher score indicating a higher incidence of PTSD symptoms. To meet criteria for PTSD, a patient must have: 1. A traumatic event 2. At least one "Re-experiencing" symptom 3. At least one "Avoidance" symptom 4. At least two "Negative alterations in cognitions and mood" symptoms 5. At least two "Alterations in arousal and reactivity" symptoms 6. The trauma must last at least a month 7. The trauma must cause impairment A clinically significant response is defined as at least a 50% decrease in the CAPS-5.
Remission From PTSD as Measured by the Clinician-Administered PTSD Scale (CAPS-5)	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	The CAPS-5 is a 30-item structured interview that can be used to make current (past month) diagnosis of PTSD, make lifetime diagnosis of PTSD, and assess PTSD symptoms over the past week. The assessor combines information about frequency and intensity of an item into a single severity rating. CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms; the range of the scores is 0-80; with a higher score indicating a higher incidence of PTSD symptoms. To meet criteria for PTSD, a patient must have: 1. A traumatic event 2. At least one "Re-experiencing" symptom 3. At least one "Avoidance" symptom 4. At least two "Negative alterations in cognitions and mood" symptoms 5. At least two "Alterations in arousal and reactivity" symptoms 6. The trauma must last at least a month 7. The trauma must cause impairment Remission is defined as a CAPS-5 score less than or equal to 29.
Number of Participants With Treatment-emergent Adverse Events and Serious Adverse Events	Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)	This measure counts the number of participants with adverse events and serious adverse events.
Functional Connectivity Changes (Measured by Resting-state Functional Magnetic Resonance Imaging) of the Targeted Brain Network(s) Following rTMS Treatment	Baseline to three weeks (the conclusion of rTMS treatment)	Resting-state brain networks were identified using functional Magnetic Resonance Imaging. Any changes in the the targeted brain network (e.g. the sub-genual cingulate cortex) were reported using functional connectivity Z-scores. Functional connectivity Z-score indicates the number of standard deviations away from the baseline mean. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean, and lower connectivity, and positive numbers indicate values higher than the baseline mean, and higher connectivity