Real-time fMRI feedback guides self-generated cognition toward upregulation of hippocampal activity.

The hippocampus is crucial for mental time travel and visuospatial processing, with dysfunction having major implications for aging, stress resilience, and mental health. While external neurostimulation methods can modulate hippocampal activity, effective real-world interventions require flexible, self-guided approaches. Building on recent demonstrations of endogenous hippocampal control in rodents, we show in two real-time fMRI neurofeedback studies (n = 141) that human participants can harness self-generated mental states to upregulate hippocampal activity within a single training session. Crucially, engagement in hippocampus-relevant mental strategies did not predict upregulation capacity in a yoked sham-control group that received similar task instructions but no feedback correlated with hippocampal state fluctuations. This suggests that contingent feedback is required to identify or refine cognitive content that effectively upregulates hippocampal activity. Training with contingent feedback significantly enhanced upregulation capacity across all hippocampal subfields compared with the sham protocol, and this effect was absent in the untargeted yet functionally connected entorhinal cortex. Across both studies, successful hippocampal upregulation was associated with co-activation of medial temporal and default-mode network regions. Additionally, successful hippocampal upregulation during later training runs was associated with multivariate pattern shifts in this hippocampal-upregulation network at event boundaries during subsequent movie viewing, suggesting that neurofeedback training may alter boundary-related neural representations during naturalistic experience. These findings reveal that contingent hippocampal feedback can facilitate the acquisition of self-neuromodulation via mental strategies, with potential implications for interventions targeting hippocampus-dependent functions.