High-frequency oscillations in the mammalian brain after ketamine and other NMDA receptor antagonists.

Subanesthetic doses of ketamine produce rapid psychotomimetic and long-lasting antidepressant effects, yet its mechanisms remain unclear. Neurophysiological recordings in freely moving rodents reveal that ketamine and other NMDAR antagonists markedly enhance high-frequency oscillations (HFO, >100 Hz) across olfactory and frontostriatal brain regions. This rhythm is remarkably coherent across distinct regions, modulated by slower oscillations, and driven largely by respiration-locked olfactory bulb activity. Similar activity has been observed in other mammals. This review is the first synthesis of studies on NMDAR antagonist-enhanced HFO, identifying gaps and urging more human research.

Study at a glance

Abstract

Subanesthetic doses of ketamine produce complex neuropsychiatric effects, which include rapid psychotomimetic symptoms and antidepressant effects that can last several weeks. Despite over 60 years of research, the mechanism(s) of action underlying ketamine's effects in the brain remains largely mysterious. Neurophysiological field potential recordings provide a direct window into brain activity, with different frequency bands reflecting functionally distinct neural networks. Two decades ago, we reported on the existence of high-frequency oscillations (HFO, >100 Hz) in freely moving rodents that were markedly enhanced by subanesthetic doses of ketamine. Since then, a large body of evidence has shown that HFO after ketamine (and other N-methyl-d-aspartate receptor (NMDAR) antagonists) are largely wake-related and prominent across diverse olfactory and frontostriatal brain regions. This rhythm, which is remarkably coherent across distinct regions, is modulated by slower oscillations with respiration-locked olfactory bulb activity a major driving force behind it. Similar activity has been reported in vivo in a variety of mammals with preclinical validity. This review is the first synthesis of studies reporting on the NMDAR antagonist-enhanced HFO rhythm. We identify current gaps and provide suggestions for future research, including the urgent need for more human studies.