Causally probing the role of the human hippocampus in fear discrimination: A precision functional mapping guided TMS study in individuals with post-traumatic stress symptoms

Abstract Fear overgeneralization is a potential pathogenic mechanism of anxiety-related disorders. A dominant model posits that overgeneralization occurs when the hippocampus fails to distinctly encode benign stimuli with insufficient similarity to previously encountered fear cues, triggering excessive retrieval of stored fear representations. This model has cross-species support but has not been causally tested in humans. A developing literature demonstrates that hippocampal network targeted transcranial magnetic stimulation (HNT-TMS) can strengthen hippocampal-dependent memory encoding. Building on this literature, we hypothesized that HNT-TMS would strengthen encoding of perceptually similar stimuli and thereby reduce retrieval errors (i.e., sharpen discrimination) in participants with post-traumatic stress symptoms. We predicted that this effect would emerge for fear stimuli as measured by the Farmer Task and neutral stimuli as measured by the Mnemonic Similarity Task. Continuous theta-burst stimulation (cTBS) was delivered to individualized left posterior-parietal targets derived via precision functional mapping, seed-based connectivity, and electric-field modeling methods. A vertex control target was also stimulated in a within-subject design (final N = 25). Multilevel models did not reveal significant interactions between stimulation target and fear or neutral stimulus discrimination. However, HNT-TMS strengthened fear discrimination in participants with lower sensitization, indexed by responsivity to a control stimulus perceptually unrelated to the CS+. Sensitization reflects indiscriminate fear responding unrelated to CS + similarity and is not expected to engage the hippocampal CS + matching function. Our findings therefore indicate that HNT-TMS may selectively sharpen fear discrimination when the hippocampal CS + matching function is more strongly engaged.