Modulation of functional networks in patients with post-traumatic stress disorder

Over 12 million Americans are diagnosed with post-traumatic stress disorder (PTSD). Neuroimaging research has identified several brain regions that play a role in this disorder, but the region that has garnered the most attention in PTSD research is the hippocampus (primarily known for its role in memory). Although the hippocampus has been widely implicated in PTSD, this research has been limited to reporting correlational rather than causal relationships. Researching causal relationships between brain regions and their associated functions is necessary in order to determine whether dysfunction of a specific brain region causes particular symptoms, or whether the symptoms cause the neural dysfunction (or both). Such information is critical for the development of neurobiologically-motivated treatments, which is particularly needed for disorders such as PTSD, given the substantial number of patients who either drop out of treatment or do not respond. Extending research on PTSD to include tests of causal brain-behavior relationships would be possible via targeted, experimental manipulation of hippocampal function; however, this approach has been prohibitively challenging in humans due to the subcortical (deep) location of the hippocampus within the brain. The proposed project thus aims to target and modify hippocampal function for the first time in PTSD using an innovative, effective, and safe approach that has never before been applied to this group of patients. This new method, termed “Hippocampal-Cortical Network Stimulation” (HCN-Stim), uses a form of noninvasive brain stimulation referred to as transcranial magnetic stimulation (TMS). HCN-Stim does not stimulate the hippocampus directly, but instead makes use of its placement within a network of highly connected brain regions (the “hippocampal-cortical network”), some of which are located in greater proximity to the brain’s surface. These stimulated regions on the brain’s surface are identified individually in each subject using functional magnetic resonance imaging (fMRI), with an individually-mapped hippocampal target as the seed. HCN-Stim has shown reliable increases in connectivity of the hippocampus with other areas of the hippocampal-cortical network, as well as significant long-term enhancements in memory performance. In the proposed study, patients will undergo five sessions of HCN-Stim using an established protocol, with stimulation effects assessed behaviorally (via a standard, laboratory-based contextual fear learning task) and neurophysiologically (via fMRI connectivity measures). The use of a contextual fear learning task will allow us to test a proposed mechanism for hippocampal involvement in PTSD, as deficits in contextual fear processing have long been associated with abnormal hippocampal function in this disorder, but a causal role has never been tested. Specificity of the stimulation approach will be established by including a matched control condition (TMS delivered using the same parameters but to a control location, outside of the hippocampal-cortical network). Given the already robust evidence that HCN-Stim enhances hippocampal network connectivity, together with the well-established role of the hippocampus in PTSD, HCN-Stim may be a promising method of modulating the hippocampal-cortical network in PTSD patients in order to probe its causal role in this disorder. Results also hold significant translational potential for a novel, stimulation-based approach to PTSD treatment.