Ketamine Alters Tuning of Neural and Behavioral Spatial Working Memory Precision
Article
Rahmati, M, Moujaes, F, Suljič, NP et al. (2026). Ketamine Alters Tuning of Neural and Behavioral Spatial Working Memory Precision
. BIOLOGICAL PSYCHIATRY, 10.1016/j.biopsych.2026.09.016
Rahmati, M, Moujaes, F, Suljič, NP et al. (2026). Ketamine Alters Tuning of Neural and Behavioral Spatial Working Memory Precision
. BIOLOGICAL PSYCHIATRY, 10.1016/j.biopsych.2026.09.016
Background Working memory (WM) is a key element of cognition that depends on the accurate internal representation of stimuli and is often impaired in psychiatric disorders, including schizophrenia. Previous human neuropharmacological studies with ketamine suggest that glutamate NMDA receptors (NMDARs) are critical for spatial WM (sWM), with NMDAR antagonism attenuating task-evoked neural activation and reducing WM accuracy. At the cellular level, animal studies and cortical microcircuit models hypothesize that NMDAR antagonism impairs sWM by decreasing the specificity of neuronal responses to spatial locations through broadened spatial tuning. Testing the relevance of this mechanism in humans remains a vital gap in our understanding of sWM and is critical for designing better treatments for WM impairments. Methods To overcome the challenges of measuring neuronal responses invasively in humans, we combined pharmacological manipulation and computational functional magnetic resonance imaging to show that ketamine broadens neural spatial tuning in healthy adults ( N = 40). Specifically, we modeled population neuron-level representations rather than traditionally examined changes in blood oxygen level–dependent (BOLD) activation. Results Broader neural tuning across visual perception and WM networks was linked to poorer sWM performance under ketamine, implicating tuning changes in sWM deficits. Furthermore, compared with the overall magnitude of BOLD activation, ketamine-induced changes in tuning were more consistent across individuals and brain regions, suggesting a collective effect of ketamine on neural tuning across spatially selective regions. Conclusions These findings provide the first empirical evidence linking altered neuronal tuning to NMDAR antagonism and sWM impairments in humans, advancing a mechanistic understanding of glutamatergic mechanisms underlying sWM and related deficits in neuropsychiatric disorders.
