Relationship Between Replay-Associated Ripples and Hippocampal N-Methyl-D-Aspartate Receptors: Preliminary Evidence From a PET-MEG Study in Schizophrenia

Abstract

Abstract Background and Hypotheses Hippocampal replay and associated high-frequency ripple oscillations are among the best-characterized phenomena in resting brain activity. Replay/ripples support memory consolidation and relational inference, and are regulated by N-methyl-D-aspartate receptors (NMDARs). Schizophrenia has been associated with both replay/ripple abnormalities and NMDAR hypofunction in both clinical samples and genetic mouse models, although the relationship between these 2 facets of hippocampal function has not been tested in humans. Study Design Here, we avail of a unique multimodal human neuroimaging data set to investigate the relationship between the availability of (intrachannel) NMDAR binding sites in hippocampus, and replay-associated ripple power, in 16 participants (7 nonclinical participants and 9 people with a diagnosis of schizophrenia, PScz). Each participant had both a [18F]GE-179 positron emission tomography (PET) scan (to measure NMDAR availability, VT) and a magnetoencephalography (MEG) scan (to measure offline neural replay and associated high-frequency ripple oscillations, using Temporally Delayed Linear Modeling). Study Results We show a positive relationship between hippocampal NMDAR availability and replay-associated ripple power. This linkage was evident across control participants (r(5) = .94, P = .002) and PScz (r(7) = .70, P = .04), with no group difference. Conclusions Our findings provide preliminary evidence for a relationship between hippocampal NMDAR availability and replay-associated ripple power in humans, and haverelevance for NMDAR hypofunction theories of schizophrenia.