Ketamine, a World Health Organization Essential Medicine, is widely used at varying doses for sedation, pain control, general anesthesia, and as a therapy for treatment-resistant depression. While scientists know its target in brain cells and have observed how it affects brain-wide activity, they haven’t known entirely how the two are connected. A new study by a research team spanning four Boston-area institutions uses computational modeling of previously unappreciated physiological details to fill that gap and offer new insights into how ketamine works.
“This modeling work has helped decipher likely mechanisms through which ketamine produces altered arousal states as well as its therapeutic benefits for treating depression,” says co-senior author Emery N. Brown, the Edward Hood Taplin Professor of Computational Neuroscience and Medical Engineering at The Picower Institute for Learning and Memory at MIT, as well as an anesthesiologist at Massachusetts General Hospital and a professor at Harvard Medical School.
The researchers from MIT, Boston University (BU), MGH, and Harvard University say the predictions of their model, published May 20 in Proceedings of the National Academy of Sciences, could help physicians make better use of the drug.
“When physicians understand what's mechanistically happening when they administer a drug, they can possibly leverage that mechanism and manipulate it,” says study lead author Elie Adam, a research scientist at MIT who will soon join the Harvard Medical School faculty and launch a lab at MGH. “They gain a sense of how to enhance the good effects of the drug and how to mitigate the bad ones.”
Blocking the door
The core advance of the study involved biophysically modeling what happens when ketamine blocks the “NMDA” receptors in the brain’s cortex — the outer layer where key functions such as sensory processing and cognition take place. Blocking the NMDA receptors modulates the release of excitatory neurotransmitter glutamate.
When the neuronal channels (or doorways) regulated by the NMDA receptors open, they typically close slowly (like a doorway with a hydraulic closer that keeps it from slamming), allowing ions to go in and out of neurons, thereby regulating their electrical properties, Adam says. But, the channels of the receptor can be blocked by a molecule. Blocking by magnesium helps to naturally regulate ion flow. Ketamine, however, is an especially effective blocker.
Blocking slows the voltage build-up across the neuron’s membrane that eventually leads a neuron to “spike,” or send an electrochemical message to other neurons. The NMDA doorway becomes unblocked when the voltage gets high. This interdependence between voltage, spiking, and blocking can equip NMDA receptors with faster activity than its slow closing speed might suggest. The team’s model goes further than ones before by representing how ketamine’s blocking and unblocking affect neural activity.
“Physiological details that are usually ignored can sometimes be central to understanding cognitive phenomena,” says co-corresponding author Nancy Kopell, a professor of mathematics at BU. “The dynamics of NMDA receptors have more impact on network dynamics than has previously been appreciated.”
With their model, the scientists simulated how different doses of ketamine affecting NMDA receptors would alter the activity of a model brain network. The simulated network included key neuron types found in the cortex: one excitatory type and two inhibitory types. It distinguishes between “tonic” interneurons that tamp down network activity and “phasic” interneurons that react more to excitatory neurons.
The team’s simulations successfully recapitulated the real brain waves that have been measured via EEG electrodes on the scalp of a human volunteer who received various ketamine doses and the neural spiking that has been measured in similarly treated animals that had implanted electrode arrays. At low doses, ketamine increased brain wave power in the fast gamma frequency range (30-40 Hz). At the higher doses that cause unconsciousness, those gamma waves became periodically interrupted by “down” states where only very slow frequency delta waves occur. This repeated disruption of the higher frequency waves is what can disrupt communication across the cortex enough to disrupt consciousness.
