Neuromodulation of the Hippocampus to Reduce Intrusive Re-Experiencing in PTSD: A Randomized Controlled Trial

Characterization and Modulation of Traumatic Memories in PTSD Patients Using Transcranial Magnetic Stimulation (TMS)

The goal of this clinical trial is to learn if non-invasive neurostimulation of memory-related brain areas works to treat intrusive memory symptoms in adults patients with posttraumatic stress disorder (PTSD). It will also learn about the effect of this neuromodulation procedure on reorganization of memory-related brain networks. The main questions it aims to answer are:

Does neuromodulation lower the number of times and the emotional severity participants intrusive memories? Does neuromodulation reduces the overall severity of PTSD? Researchers will compare neuromodulation targeting the hippocampus (a memory-related brain structure) to a control stimulation in an area not related to memory processes to see if hippocampus neuromodulation works to treat intrusive trauma memories and PTSD.

Participants will:

1. Undergo magnetic resonance imaging (MRI) scans before and after neuromodulation to: a) determine a personalized neuromodulation target; and b) to measure changes in brain function from before to after treatment.
2. Receive hippocampus neuromodulation or a control neuromodulation once a week for 5 weeks.

Keep a daily diary of their symptoms and the number of times they experience intrusive trauma memories.

Intrusive trauma memories are a hallmark of posttraumatic stress disorder (PTSD), and the least treatment responsive. Thus, revealing neurocognitive mechanisms associated with intrusive trauma memories has been indexed a priority. Prior work shows that targeting hippocampal circuitry modulates functional connectivity among distributed cortical-hippocampal network regions and alters memory performance in healthy participants. In the current clinical trial we test hypotheses on the clinical effects of such stimulation in a two-arms randomized controlled trial: Trauma memory reactivation + targeted hippocampal transcranial magnetic stimulation TMS (R-H-TMS) and Trauma memory reactivation + Control TMS (over the SMA; R-C-TMS). We will test a) Hippocampus seed-based connectivity patterns - revealing the impact of the targeted stimulation on extended memory brain networks; and b) frequency and severity of intrusive memory symptoms. The R-H-TMS vs. R-C-TMS contrast will speak to specificity of the noted effects to hippocampal stimulation.

Inclusion Criteria:

• Aged of 20-65 years.
• Meet a diagnosis of PTSD according to DSM-5 as tested by a structured clinical interview (Clinician-Administered PTSD Scale for DSM-5 - CAPS-5).
• CAPS-5 total score greater or equal to 33.
• Endorsement of intrusive symptoms (flashbacks, nightmares, or intrusive memories) with a frequency of at least 3 times a week.
• Meeting the accepted criteria for inclusion in an MRI examination.

Exclusion Criteria:

• Meeting a diagnosis of Complex PTSD or personality disorder.
• Psychotic disorder, bipolar disorder, or a developmental neuropsychological disorder (autism, mental retardation).
• Use of psychiatric medications (except for the medications listed in section 4.a of the study protocol if the medication dosage is stable in the last three months and does not change during the study.
• Exclusion rules in TMS research (see guidelines).
• Use of the following drugs: imipramine, amitriptyline, doxepin, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, (MDMA, ecstasy), phencyclidine (PCP, angel's dust), ketamine, gamma- hydroxybutyrate (GHB), alcohol, theophylline
• Epilepsy or use of anti-epileptic drugs.
• Traumatic head injuries or head surgery.
• Implanted metallic body (except fillings/amalgam bites/orthodontic fixations approved for MRI), electrodes or a pacemaker.
• Migraines
• Pregnant women
• Hearing problems
• Drinking alcohol 24 hours before the TMS session
• Repeated episodes of fainting with loss of consciousness and/or an event of fainting with loss of consciousness in the past year.
• The accepted exclusion criteria for an MRI examination