Pathophysiological Understanding and Treatment of PTSD: an rTMS Approach

NCT03840369 | Completed

• 1 other identifier: REB18-1976
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

In Canada, the prevalence of PTSD is approximately 12%, similar to Canadian military personnel. Current treatments for PTSD are limited in efficacy and durability - indicating a dire need for novel interventions in this population. Transcranial magnetic stimulation (TMS) has a high degree of safety and has been studied as an intervention for many mental health and neurological conditions; even showing initial promise for PTSD. We propose to study this further in a randomized sham controlled trial of TMS for PTSD.

Conditions

Stress Disorders, Post-Traumatic; Brain Injuries; Transcranial Magnetic Stimulation; Magnetic Resonance Spectroscopy; Biomarkers; Depression, Anxiety

Outcome Measures

Primary Outcomes (1)

• Effect of 20-session rTMS Intervention to the DMPFC versus DLPFC on PCL Overall Score, Stratified by Verbal Memory Task Scores

  To determine whether patients with PTSD\_LVMS have a greater response to a 20-day low frequency rTMS treatment protocol of the right DMPFC compared to the DLPFC, and if patients with PTSD\_NVMS respond better to a 20-day low frequency TMS treatment protocol of the right DLPFC compared to the DMPFC as measured by the clinician administered PTSD scale for DSM-5 (CAPS-5) in male and female participants (military personnel and civilians) at 4 weeks and 1 month post-treatment.

  Change in PCL-5 score at pre-treatment appointment, compared with the score at 1 week, upon study completion, and 4 weeks post-rTMS treatment.

Secondary Outcomes (1)

• Serum BDNF, Glutamate, Glutathione, and MR Spectroscopy pre and post rTMS intervention

  Change in serum BDNF, glutamate, and glutathione at the pre-treatment appointment compared with 1 week into treatment and upon study completion.

Other Outcomes (1)

• Effect of rTMS on Quality of Life After Brain Injury survey (QOLIBRI), headaches, anxiety and depression in individuals with PTSD

  Change in QOLIBRI score at the pre-treatment appointment compared with 1 week, upon study completion, and 4 weeks post treatment.

Study Arms (2)

rTMS to the Right Dorsolateral Prefrontal Cortex

EXPERIMENTAL

Patients will engage in a one-week placebo control lead-in (5 treatments) and then a four-week treatment protocol (20 treatments) to the right Dorsolateral Prefrontal Cortex (DLPFC). The right DLPFC will be located with MR brain scans and the BrainSight TMS neuronavigation software. The intensity of the rTMS will be 100-120% of resting motor threshold amplitude, 1500 pulses applied consistently with a frequency of 1 Hz.

Device: Repetitive Transcranial Magnetic Stimulation to Right Dorsolateral Prefrontal Cortex; Device: Sham Repetitive Transcranial Magnetic Stimulation

rTMS to the Right Dorsomedial Prefrontal Cortex

EXPERIMENTAL

Patients will engage in a one-week placebo control lead-in (5 treatments) and then a four-week treatment protocol (20 treatments) to the right Dorsomedial Prefrontal Cortex (DMPFC). The right DMPFC will be located with MR brain scans and the BrainSight TMS neuronavigation software. The intensity of the rTMS will be 100-120% of resting motor threshold amplitude, 1500 pulses applied consistently with a frequency of 1 Hz.

Device: Sham Repetitive Transcranial Magnetic Stimulation; Device: Repetitive Transcranial Magnetic Stimulation to Right Dorsomedial Prefrontal Cortex

Interventions

Repetitive Transcranial Magnetic Stimulation to Right Dorsolateral Prefrontal Cortex DEVICE

Transcranial magnetic stimulation (TMS) works by delivering a magnetic pulse to a focal brain region. TMS has a high degree of safety and has been studied as an intervention for many mental health and neurological conditions. Repetitive TMS (rTMS) delivers pulses at a set time interval in order to modulate neural activity in that region.

Also known as: rTMS to DLPFC

rTMS to the Right Dorsolateral Prefrontal Cortex

Sham Repetitive Transcranial Magnetic Stimulation DEVICE

The sham TMS coil will make a similar sound to the real rTMS coil, but will not deliver a magnetic pulse. This is a no-treatment device.

rTMS to the Right Dorsolateral Prefrontal Cortex; rTMS to the Right Dorsomedial Prefrontal Cortex

Repetitive Transcranial Magnetic Stimulation to Right Dorsomedial Prefrontal Cortex DEVICE

Transcranial magnetic stimulation (TMS) works by delivering a magnetic pulse to a focal brain region. TMS has a high degree of safety and has been studied as an intervention for many mental health and neurological conditions. Repetitive TMS (rTMS) delivers pulses at a set time interval in order to modulate neural activity in that region.

Also known as: rTMS to DMPFC

rTMS to the Right Dorsomedial Prefrontal Cortex

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult participants represent a typically developing nervous system as a more reliable target for this stage of research.
• The presence of a PTSD diagnosis made by a physician will ensure participants are experiencing significant symptomatology and may benefit from treatment.
• The cutoff score on the PCL-5 will ensure that participants are experiencing similar levels of symptoms to each other.
• Need to have tried at least two types of treatment in the past

You may not qualify if:

• Metal in head/neck/eye is a contraindication to safety in the MRI scanner and TMS protocol.
• Women who are pregnant will not be included in the study due to potential risk of seizure during TMS. To determine if a patient is pregnant we will ask when their last menstrual cycle occurred. If there is a possibility of pregnancy, we will ask the participant to follow-up with their family doctor to confirm. We will then ask the participant to provide a written note from their treating practitioner stating they are not pregnant.
• Active suicidality
• Wellbutrin or benzodiazepine intake of more than 200mg/day, or more than 15 mg of Zopiclone per day as these medications lower seizure threshold
• Trauma experienced less than a year ago and/or trauma experienced only as a child
• Drug and/or alcohol abuse within the last 3 months (diagnosed by Canadian guidelines)
• Diagnosed schizophrenia, untreated bipolar disorder, or psychosis

Sponsors & Collaborators

• University of Calgary: lead
• Defence Research and Development Canada: collaborator

Study Sites (1)

Foothill Medical Centre

Calgary, Alberta, Canada

Location

Related Publications (25)

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• Vucic S, Kiernan MC. Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease. Neurotherapeutics. 2017 Jan;14(1):91-106. doi: 10.1007/s13311-016-0487-6.

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• Kozel FA, Motes MA, Didehbani N, DeLaRosa B, Bass C, Schraufnagel CD, Jones P, Morgan CR, Spence JS, Kraut MA, Hart J Jr. Repetitive TMS to augment cognitive processing therapy in combat veterans of recent conflicts with PTSD: A randomized clinical trial. J Affect Disord. 2018 Mar 15;229:506-514. doi: 10.1016/j.jad.2017.12.046. Epub 2017 Dec 28.

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• Fryml LD, Sahlem G, Fox J, Short EB. The role of rTMS for patients with severe PTSD and depression. Evid Based Ment Health. 2018 Feb;21(1):39-40. doi: 10.1136/eb-2017-102819. Epub 2018 Jan 5. No abstract available.

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• Osuch EA, Benson BE, Luckenbaugh DA, Geraci M, Post RM, McCann U. Repetitive TMS combined with exposure therapy for PTSD: a preliminary study. J Anxiety Disord. 2009 Jan;23(1):54-9. doi: 10.1016/j.janxdis.2008.03.015. Epub 2008 Mar 28.

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• Wang HN, Bai YH, Chen YC, Zhang RG, Wang HH, Zhang YH, Gan JL, Peng ZW, Tan QR. Repetitive transcranial magnetic stimulation ameliorates anxiety-like behavior and impaired sensorimotor gating in a rat model of post-traumatic stress disorder. PLoS One. 2015 Feb 6;10(2):e0117189. doi: 10.1371/journal.pone.0117189. eCollection 2015.

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• Philip NS, Ridout SJ, Albright SE, Sanchez G, Carpenter LL. 5-Hz Transcranial Magnetic Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depression. J Trauma Stress. 2016 Feb;29(1):93-6. doi: 10.1002/jts.22065. Epub 2016 Jan 7.

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• Pradhan B, Kluewer D'Amico J, Makani R, Parikh T. Nonconventional interventions for chronic post-traumatic stress disorder: Ketamine, repetitive trans-cranial magnetic stimulation (rTMS), and alternative approaches. J Trauma Dissociation. 2016;17(1):35-54. doi: 10.1080/15299732.2015.1046101. Epub 2015 Jul 10.

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• Watts BV, Landon B, Groft A, Young-Xu Y. A sham controlled study of repetitive transcranial magnetic stimulation for posttraumatic stress disorder. Brain Stimul. 2012 Jan;5(1):38-43. doi: 10.1016/j.brs.2011.02.002. Epub 2011 Mar 3.

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• Nam DH, Pae CU, Chae JH. Low-frequency, Repetitive Transcranial Magnetic Stimulation for the Treatment of Patients with Posttraumatic Stress Disorder: a Double-blind, Sham-controlled Study. Clin Psychopharmacol Neurosci. 2013 Aug;11(2):96-102. doi: 10.9758/cpn.2013.11.2.96. Epub 2013 Aug 26.

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• Oznur T, Akarsu S, Celik C, Bolu A, Ozdemir B, Akcay BD, Ozselek S, Bozkurt A, Ozmenler KN. Is transcranial magnetic stimulation effective in treatment-resistant combat related posttraumatic stress disorder? Neurosciences (Riyadh). 2014 Jan;19(1):29-32.

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• Berlim MT, Van Den Eynde F. Repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex for treating posttraumatic stress disorder: an exploratory meta-analysis of randomized, double-blind and sham-controlled trials. Can J Psychiatry. 2014 Sep;59(9):487-96. doi: 10.1177/070674371405900905.

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• Liu G, Feng D, Wang J, Zhang H, Peng Z, Cai M, Yang J, Zhang R, Wang H, Wu S, Tan Q. rTMS Ameliorates PTSD Symptoms in Rats by Enhancing Glutamate Transmission and Synaptic Plasticity in the ACC via the PTEN/Akt Signalling Pathway. Mol Neurobiol. 2018 May;55(5):3946-3958. doi: 10.1007/s12035-017-0602-7. Epub 2017 May 26.

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• Moshe H, Gal R, Barnea-Ygael N, Gulevsky T, Alyagon U, Zangen A. Prelimbic Stimulation Ameliorates Depressive-Like Behaviors and Increases Regional BDNF Expression in a Novel Drug-Resistant Animal Model of Depression. Brain Stimul. 2016 Mar-Apr;9(2):243-50. doi: 10.1016/j.brs.2015.10.009. Epub 2015 Nov 10.

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• Etkin A, Maron-Katz A, Wu W, Fonzo GA, Huemer J, Vertes PE, Patenaude B, Richiardi J, Goodkind MS, Keller CJ, Ramos-Cejudo J, Zaiko YV, Peng KK, Shpigel E, Longwell P, Toll RT, Thompson A, Zack S, Gonzalez B, Edelstein R, Chen J, Akingbade I, Weiss E, Hart R, Mann S, Durkin K, Baete SH, Boada FE, Genfi A, Autea J, Newman J, Oathes DJ, Lindley SE, Abu-Amara D, Arnow BA, Crossley N, Hallmayer J, Fossati S, Rothbaum BO, Marmar CR, Bullmore ET, O'Hara R. Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder. Sci Transl Med. 2019 Apr 3;11(486):eaal3236. doi: 10.1126/scitranslmed.aal3236.

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• Kozel FA. Clinical Repetitive Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder, Generalized Anxiety Disorder, and Bipolar Disorder. Psychiatr Clin North Am. 2018 Sep;41(3):433-446. doi: 10.1016/j.psc.2018.04.007.

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Related Links

• National Center for PTSD

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic; Brain Injuries; Depression; Anxiety Disorders

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Behavioral Symptoms; Behavior

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Group 1: Treatment of the right dorsolateral prefrontal cortex Group 2: Treatment of the right dorsomedial prefrontal cortex

Study Record Dates

• First Submitted: February 7, 2019
• First Posted: February 15, 2019
• Study Start: June 1, 2020
• Primary Completion: February 18, 2022
• Study Completion: March 18, 2022
• Last Updated: November 4, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)