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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

human healthyhealthybehaviour

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.

Specieshuman
Subjects23 participants
Sessions per subject2
Randomisednot reported
Blindingsingle
Sham / controlactive control site
Auditory controlnot reported
Readout timingoffline
Anaesthesianot applicable
Readoutsbehaviour — Goalkeeper Game: dependence of persist-with-prediction behaviour on recent paired-transition history (experience-based and inference-based learning)
Direction of effectmixed or unclearHippocampal TUS reduced both experience-based and inference-based learning compared with white matter control, abolishing structure-based inference; preference learning was unaffected.
Adverse eventsnot reportedPost-TUS questionnaire at session end and 24 h later; k-Plan simulations gave MI below 1.9 and thermal dose not above 0.25 CEM43.

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 ✓

Pulse timing
Waveformtheta 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✓✓✓
Pressure and intensity, by domain
Free-field pressure (kPa)not reported
Free-field Isppa (W/cm²)75✓✓✓⚑
Free-field Ispta (W/cm²)not reported
In-situ estimatesimulationmean or range across subjects
In-situ pressure (kPa)not reported
In-situ Isppa (W/cm²)5✓✓✓⚑
In-situ Ispta (W/cm²)not reported
Protocol, in the paper’s words

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.