Ketamine Alters Tuning of Neural and Behavioral Spatial Working Memory Precision
Masih Rahmati, Flora Moujaes, Nina Purg Suljič, Jie Lisa Ji, Lucie Berkovitch, Kangjoo Lee, Clara Fonteneau, Charles H. Schleifer, Brendan D. Adkinson, Aleksandar Savič, Nicole Santamauro, Zailyn Tamayo, Caroline Diehl, Antonija Kolobaric, Morgan Flynn, Terry Camarro, Clayton E. Curtis, Grega Repovš, Sarah K. Fineberg, Peter T. Morgan, Katrin H. Preller, John H. Krystal, John D. Murray, Youngsun T. Cho, Alan Anticevic
bioRxiv Preprint Server February 10, 2025 preprint DOI: 10.1101/2025.02.10.637233 via bioRxiv
Summary
AI-generated from the abstractWorking memory deficits in disorders like schizophrenia may stem from disrupted brain cell tuning. Using fMRI, researchers found that ketamine, which blocks NMDA receptors, broadens neural spatial tuning in healthy people, reducing the precision of brain responses across visual, parietal, and frontal areas and worsening spatial working memory accuracy. These tuning changes were more consistent across individuals and brain regions than overall activation changes and correlated with memory performance. The results link NMDA receptor disruption to altered brain circuit dynamics and memory impairment, offering a target for developing treatments.
Study at a glance
| Characteristics | Pharmacological fMRI study |
|---|---|
| Population | Healthy humans |
| Intervention | Ketamine |
| Keywords | Memory deficits:memory problems Poorer memory Memory impairment Memory loss Spatial tuning |
| Citations | 1 |
| Key finding | Ketamine broadens neural spatial tuning, attenuates activation across multiple brain regions, and worsens spatial working memory performance in healthy humans. |
Abstract
Deficits in working memory (WM) are a hallmark of neuropsy-chiatric disorders such as schizophrenia, yet their neurobiological basis remains poorly understood. Glutamate N-methyl-D-aspartate receptors (NMDARs) are critical for spatial WM (sWM), with NMDAR antagonist ketamine known to attenuate task-evoked activation and reduce sWM accuracy. Cortical microcircuit models hypothesize that NMDAR antagonism impairs sWM by broadening neural spatial tuning, but this mechanism has not been directly tested in humans. Using a pharmacological fMRI approach, we showed how ketamine broadened neural spatial tuning, attenuated activation across visual, parietal, and frontal areas, and worsened sWM performance in healthy humans. Ketamine-induced changes in tuning were more consistent across individuals and brain regions than changes in overall activation and correlated with individual differences in sWM performance. These findings provide empirical evidence linking NMDAR antagonism to disruptions in cortical microcircuit dynamics, the resulting neural tuning alterations, and sWM impairments, advancing frameworks for therapeutic development.