Causal necessity of hippocampus for structure-based inference in learning
Deng Pan, Simone D'Ambrogio, Naomi Kingston, Miruna Rascu, Pranav Sankhe, Shuyi Luo, Miriam Klein-Flügge, Ali Mahmoodi, Matthew Rushworth
2025 · 10.21203/rs.3.rs-7320179/v1
Abstract
When meeting new individuals or encountering known individuals in new circumstances, we intuitively map out their relationships – not merely by direct experience, but by quickly inferring new connections based on prior relational knowledge. Using a novel task, we demonstrated that participants indeed employ knowledge of relational structures to facilitate learning of new relationships in a changing environment. Computational modelling revealed that participants leveraged relational knowledge to support inference, thus facilitating learning. Whole brain neuroimaging identified a uniquely robust representation of relational structure in the hippocampus. Neural networks trained on similar tasks demonstrated the emergence of relational structure representations, resembling those found in hippocampus. Lesioning network units sustaining such representations disrupted structure-based inference and predicted hippocampus’s essential role. Transcranial ultrasound stimulation of human hippocampus, transiently modulating its activity without affecting overlying tissue, produced similar disruption effects, empirically confirming the causal necessity of hippocampal representations for structure-based inference in learning.
Abstract via europepmc.
Exposures
Exposure 1: Bilateral hippocampus theta-burst TUS (white matter control site not listed as exposure)
Target: hippocampus — “bilateral hippocampus (HPC)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · DPX-500-4CH transducer driven by Neurofus PRO TPO ✓
| Waveform | theta burst | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 20 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓⚑ |
| Duty cycle (%) | 10pulse duration × PRF gives 10% | ✓✓✓ |
| Sonication duration (s) | 80 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 75 | ✓✓✓⚑ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 5 | ✓✓✓⚑ |
| In-situ Ispta (W/cm²) | not reported |
Theta-burst patterned TUS: 20 ms pulses every 200 ms (5 Hz), 10% duty cycle, 80 s total (400 pulses) per hemisphere, delivered sequentially to left then right hippocampus (or the white matter control site) in one session, before the Goalkeeper Game. White matter control free-field intensity was individualised between 55 and 75 W/cm2 to match the hippocampal in situ intensity.
Flags from extraction
exposures[0].timing.pulse_repetition_frequency_hz— 5 Hz stated in Results as theta-burst (5 Hz, 20-ms pulses every 200 ms); the Methods give pulse repetition interval 200 ms.exposures[0].timing.waveform— Paper calls the protocol theta-burst patterned TUS, but it is a single 5 Hz train of 20 ms pulses, with no nested burst structure.exposures[0].in_situ.isppa_w_cm2— K-Plan simulation, approximately 5 W/cm2 on average across participants (min 3 W/cm2 required for inclusion); value read from text, spread in a figure only.exposures[0].free_field.isppa_w_cm2— 75 W/cm2 is for hippocampal stimulation; the white matter control used 55 to 75 W/cm2.exposures[0].device.family— TPO named, so neurofus; transducer is the four-element DPX-500-4CH.sham_type— Control is real ultrasound to a hippocampus-unrelated white matter site, intensity-matched in situ; no inactive-transducer sham.randomised— Session order was counterbalanced; randomisation not stated.direction_of_effect— TUS to hippocampus disrupted structure-based inference relative to white matter control; authors suggest noise induction rather than clear excitation or inhibition.adverse_events— A post-TUS questionnaire was given (immediately and at 24 h) but its results are not reported in the main text.auditory_control— No auditory control or discussion of auditory confounds found.
Notes: Experiments 1 (fMRI, n=36) and 3 (behavioural, n=40) involved no ultrasound; only Experiment 2 is recorded.