Modeling the Dose-Dependent Effects of Ketamine
Post by Lani Cupo
The takeaway
Ketamine produces sedation and disassociation at low doses and anesthesia at high doses accompanied by specific patterns of brain activity characteristic of each state. Disinhibition of neural circuits leading to a global increase in excitation may underlie both low and high-dose states.
What's the science?
The dose-dependent effects of ketamine are well known, with low doses producing psychoactive effects and high doses producing anesthesia. Likewise, it is known that ketamine administration produces patterns of brain activity consistent with gamma oscillations (associated with cognitive function) at low doses, but these are interrupted by slow-delta oscillations (associated with deep sleep) at higher doses. Nevertheless, it’s still an open question how cellular processes relate to the emergence of these patterns of brain activity. This week in PNAS, Adam and colleagues present a biophysical model to simulate cellular changes and observe the effect on brain oscillatory behavior, finding that interactions between inhibitory and excitatory neurotransmitters play a role in the distinctive patterns of brain oscillations observed following ketamine exposure.
How did they do it?
First, the authors acquired electroencephalogram (EEG) data from a human volunteer and a nonhuman primate who were administered ketamine at doses sufficiently high to induce anesthesia. Then, they created a biophysical model (a simulation of biological processes) representing interactions between excitatory pyramidal neurons and inhibitory interneurons. The model focused on the activity of NMDA receptors (a major receptor of interest for ketamine), allowing NMDA receptors to change state (“open” ones can become “closed”) based on other activity in the system. Specifically, in biology, ketamine is known to block the excitatory NMDA receptors, which is interesting given the fact that low levels of ketamine create an excitatory state. It is thought that this is because ketamine blocks inhibitory neurons from firing, leading to an overall excitatory state. The authors tested this hypothesis in their biophysical model. Then, they examined what changes in the activity of neurons could explain gamma oscillations seen following ketamine exposure. Next, they examine why slow-wave delta oscillations emerge when ketamine is “increased” in the model.
What did they find?
First, the authors found characteristic patterns of EEG activity: at low levels of ketamine, gamma oscillations, representing cortical activity, were evident, whereas at higher levels of ketamine exposure, gamma oscillations were interrupted by delta waves, characteristic of sleep.
Then, using the biophysical model, the authors found evidence for the cellular mechanisms contributing to the gamma oscillations. They found evidence that ketamine blocked NMDA receptors on inhibitory interneurons, contributing to an overall excitatory state. Specifically, some neurons have a subthreshold excitatory state, meaning at baseline they are close to firing, but not quite over the threshold that makes them fire. Blocking these neurons’ NMDA receptors with ketamine can shut them down. When these neurons release inhibitory neurotransmitters, shutting them down leads to a downstream increase in excitatory neurotransmitter release, or a global increase in excitation referred to as disinhibition, because the excitatory neurons are no longer inhibited.
With their biophysical model, the authors next observed that this global excitation gave rise to gamma patterns of brain activity. This behavior is dependent on inhibitory GABA-ergic neurons, some of which are not blocked by ketamine, which can contribute to individual neurons firing at a gamma timescale. These individual neurons are synchronized across the brain, giving rise to global gamma wave activity.
In their model, the authors also find that higher doses of ketamine can induce “down-states” associated with slow-wave delta oscillations. Neurons with background excitatory states shut down under increased ketamine administration while other neurons have a reduced timescale of firing, contributing to the slower delta waves.
What's the impact?
The authors demonstrate that ketamine can produce characteristic brain waves in a biophysical model by blocking NMDA receptors. Their findings increase our understanding of the cellular mechanisms contributing to global brain activity.