Causally probing the role of the hippocampus in fear discrimination: A precision functional mapping guided, transcranial magnetic stimulation study in participants with post-traumatic stress symptoms

Background Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods Continuous theta-burst stimulation (cTBS) was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric-field modeling methods. A vertex control site was also stimulated in a within-subject, randomized controlled design. cTBS was delivered prior to two visual discrimination tasks (one fear based, one neutral). Multilevel models were used to model and test data. Subjects were undergraduates with post-traumatic stress symptoms (final N = 25). Results Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: β = 0.10 [0.04, 0.17], p = 0.001; risk ratings: β = 0.07 [0.00, 0.13], p = 0.037). Conclusions Overgeneralization is an associative process reflecting deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects non-associative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.