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While the CA3DG is viewed as a domain-general pattern separator, the parahippocampal and perirhinal cortices may play a role in content-specific (e.g., spatial or object-related) interference reduction. Recent work suggests that frontal and parietal control areas may allocate resources during mnemonic discrimination, but the evidence is still limited. Moreover, mnemonic discrimination tasks designed for humans almost exclusively use everyday items as stimuli, confounding retrieval processes with pattern separation. To address these challenges, we acquired high-resolution structural images of the medial temporal lobe, and full-brain high-resolution functional MRI data of 39 participants while they studied non-meaningful fractals with varying degrees of interference in either their spatial or object features. We found that the parahippocampal cortex contributes to interference reduction in the spatial domain, while the perirhinal cortex contributes to interference reduction in the object domain. The dorsolateral frontal and parietal regions were recruited during the encoding of interfering stimuli in both object and location domains and displayed strengthened within- and cross-network connectivity in response to interference. Contrary to our expectations, we did not find significantly increased activation in the CA3DG to similar trials relative to repeats, indicating a lack of sensitivity to small differences in interfering stimuli. Altogether, these results are in line with content-specific interference reduction in the medial temporal lobe, possibly orchestrated by frontoparietal regions, but challenge the view of the CA3DG as a universal pattern separator of the human brain.<\/jats:p>","DOI":"10.1162\/imag.a.1088","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T20:01:16Z","timestamp":1765569676000},"update-policy":"https:\/\/doi.org\/10.1162\/mitpressjournals.corrections.policy","source":"Crossref","is-referenced-by-count":3,"title":["fMRI signals of pattern separation in the neocortex and hippocampus to non-meaningful objects and their spatial location"],"prefix":"10.1162","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4259-7469","authenticated-orcid":false,"given":"Zsuzsanna","family":"Nemecz","sequence":"first","affiliation":[{"name":"Doctoral School of Psychology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, Budapest, Hungary"},{"name":"Institute of 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Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunor","family":"Kis","sequence":"additional","affiliation":[{"name":"Doctoral School of Psychology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, Budapest, Hungary"},{"name":"Institute of Psychology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, Budapest, Hungary"},{"name":"Brain Imaging Centre, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Mez\u0151","sequence":"additional","affiliation":[{"name":"Wigner Datacenter, HUN-REN Wigner Research Centre for Physics, Budapest, Hungary"},{"name":"Konkoly Observatory, HUN-REN Research Centre for Astronomy and Earth Sciences, Budapest, Hungary"},{"name":"MTA Centre of Excellence, HUN-REN Research Centre for Astronomy and Earth Sciences, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vir\u00e1g Anna","family":"Varga","sequence":"additional","affiliation":[{"name":"Institute of Psychology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, Budapest, Hungary"},{"name":"Brain Imaging Centre, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Werkle-Bergner","sequence":"additional","affiliation":[{"name":"Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Keresztes","sequence":"additional","affiliation":[{"name":"Institute of Psychology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, Budapest, Hungary"},{"name":"Brain Imaging Centre, HUN-REN Research Centre for Natural Sciences, Budapest, 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