A Mechanistic Trial of the Neurobiology of Extinction Learning and Intraparietal Sulcus Stimulation

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University of Pennsylvania




Posttraumatic Stress Disorder


Device: Sham Continuous Theta Burst Stimulation
Device: Continuous Theta Burst Stimulation to the Intraparietal Sulcus

Study type


Funder types




Details and patient eligibility


This study will be the first of its kind to explore the impact of continuous theta burst stimulation (cTBS) to the intraparietal sulcus (IPS) on arousal symptoms among patients with posttraumatic stress disorder (PTSD). The investigators will demonstrate that IPS cTBS results in significant reduction in arousal (measured by startle response) compared to sham cTBS, that IPS cTBS interacts with extinction training to further improve arousal, and that there is a dose/response effect of cTBS on arousal. The investigators will also demonstrate that IPS cTBS significantly improves retention of extinction learning, the experimental analogue of exposure therapy.

Full description

Posttraumatic stress disorder (PTSD) is associated with alterations in arousal that do not respond well to evidence-based practices. Patients with PTSD tend to fall into one of two groups in extinction training (and in exposure therapy): 1) over-engagers, where arousal is too high; and 2) under-engagers, where patients are so worried about becoming upset that they distract themselves from the task (which prevents learning). In this mechanistic clinical trial, the investigators will evaluate a strategy to augment extinction training with neuromodulation to reduce arousal and improve extinction retention. Augmenting extinction training with continuous theta burst stimulation (cTBS, a type of transcranial magnetic stimulation) delivered to the intraparietal sulcus (IPS) may lead to targeted reductions in arousal. The investigative team has shown that the IPS is a "connectivity hub" for arousal and that stimulating this region with TMS can reduce excessive arousal in healthy people. The goal for this R01 is to evaluate the main effects of IPS cTBS (versus sham cTBS, a between-subject comparison) and its interaction with extinction training (vs. neutral training) on arousal among patients with PTSD. The investigators hypothesize that reducing parietal hyperexcitability will help patients with PTSD to modulate arousal during extinction training-enough arousal to ensure that they can benefit, but not too much arousal which prevents learning. These results could translate into future opportunities for novel therapeutic targets among patients with PTSD. The specific aims are as follows: Aim 1: To evaluate the optimal dose of IPS cTBS. H1: Attenuation of startle for IPS cTBS vs. sham cTBS will plateau at 1200 pulses, the anticipated optimal cumulative dose. Aim 2: To compare the main effect of IPS cTBS and its interaction with extinction training on arousal (measured by startle response). Using a two (between group: sham vs. IPS cTBS) x 2 (within group: extinction training vs. control/neutral training) randomized controlled design among patients with PTSD (N = 120), the investigators will examine the potential benefit of cTBS and extinction training on reduction in arousal. H2a: IPS cTBS will result in greater reduction in arousal compared to sham cTBS. H2b: Participants who receive IPS cTBS will have a significantly lower difference in retention of extinction learning vs. control/neutral training (indicative of greater retention of extinction learning) compared to participants who receive sham cTBS. Secondary: The investigators will test analogous hypotheses on subjective outcomes and on cognitive outcomes and the investigators hypothesize similar directions of effects. Aim 3: To evaluate neural mechanisms of action of IPS cTBS + extinction training. Participants will complete a resting state fMRI scan on tests of retention of learning experimental visits to evaluate neural changes from training. H3: The investigators will observe attenuated activation (relative to pre-test) of the IPS for participants who received IPS cTBS compared to those who received sham cTBS.


120 estimated patients




18 to 60 years old


No Healthy Volunteers

Inclusion criteria

  • Adult aged 18-60
  • Meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for PTSD according to the Clinician-Administered PTSD Scale for DSM-5
  • Right-handed
  • No metal implants

Exclusion criteria

  • Prescription of a tricyclic antidepressant medication, given that this type of medication lowers the seizure threshold
  • Pregnancy
  • Seizure disorder or epilepsy
  • Increased risk of seizure
  • Non-English speaking
  • Any medical condition that increases risk for fMRI or cTBS
  • Medical implant
  • Hearing loss sufficient to interfere with startle
  • Claustrophobia
  • Recent medication or therapy changes (in the past 8 weeks).

Trial design

Primary purpose

Basic Science



Interventional model

Single Group Assignment


Triple Blind

120 participants in 2 patient groups, including a placebo group

Continuous theta burst stimulation to the intraparietal sulcus
Experimental group
Continuous theta burst stimulation will be delivered to the individually targeted intraparietal sulcus site at 100% RMT.
Device: Continuous Theta Burst Stimulation to the Intraparietal Sulcus
Sham continuous theta burst stimulation
Placebo Comparator group
We will use the coil's electric stimulation functionality that allows for the delivery of a brief electric pulse to the scalp simultaneous to the pulse to mimic actual stimulation.
Device: Sham Continuous Theta Burst Stimulation

Trial contacts and locations



Central trial contact

Lily A Brown, PhD

Data sourced from clinicaltrials.gov

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