Electrical, chemical, and genetic manipulation of brain circuitry in non-human animals has led to important advances in our understanding of how learned fear is acquired, how it is extinguished (lessened by experience with contradictory evidence), and how in some cases fear memories persist in eliciting stress reactions despite evidence that the feared aversive event will not recur. In the case of posttraumatic stress disorder (PTSD) in humans, evidence suggests that fear memories persist and the location of brain abnormalities underlying this persistence are consistent with the evidence for the neurobiological substrates of fear memory extinction retention gathered from non-human animal studies. By manipulating this same circuitry in humans in the context of fear extinction, it may be possible to augment the lessening of stress reactions to learned fear cues. The proposed study seeks to determine the parameters best suited for this augmentation in healthy participants using repetitive transcranial magnetic stimulation (rTMS). By testing behavioral and psychophysiological responses to learned fear cues before and after extinction in conjunction with applying rTMS to multiple brain targets, the effectiveness of each target in augmenting fear memory extinction will be evaluated. Applying rTMS interleaved with neuroimaging (functional magnetic resonance imaging) to these targeted brain areas will yield additional evidence of how induced plasticity in key brain circuits implicated in the task and in PTSD pathophysiology may relate to fear learning and extinction. Multiple targets will be evaluated this way in healthy participants before one or more can be selected for testing in patients diagnosed with PTSD. The effectiveness of rTMS to influence behavioral and psychophysiological responding to learned fear cues will thus be explored in healthy populations as a function of induced plasticity mechanisms measured in this context for the first time combining TMS/fMRI methods. The evidence gathered from these measures will provide a novel framework for evaluating neurobiological improvements in PTSD and may also support particular brain regions for targeting in a subsequent rTMS treatment.

Public Health Relevance

The goal of the proposed study is to determine ideal methods for enhancing reversal of learned fear reactions in healthy participants with transcranial magnetic stimulation (TMS) for subsequent application of the most effective stimulation parameters to patients with posttraumatic stress disorder (PTSD). The methods employed include inducing temporary brain circuit changes non-invasively in participants while they have brain activity recorded in an MRI scanner, so that the underlying brain mechanisms can be mapped on to the effectiveness of TMS to reverse stress responses to fear memories. The ultimate goal is to use this evidence to help alleviate distress from traumatic memories in PTSD patients for whom few proven effective alternatives exist to current first line therapies.

National Institute of Health (NIH)
Small Research Grants (R03)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Tuma, Farris K
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Palo Alto Veterans Institute for Research
Palo Alto
United States
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