Ketamine blocks a chemical connection between brain cells along neural pathways — which could help prevent the brain from making unnecessarily dire predictions. Illustration: Polina Shuvaeva / Getty

Rather than constantly repainting a new canvas with a picture of the surrounding world each time it takes in information, the human brain appears to build a working model supported by predictions constantly checked and rechecked against the sights and sounds it already expects.

Researchers in the lab of UW–Madison psychology and neuroscience professor Yuri Saalmann demonstrated the top-down nature of this world view by disrupting it with tiny doses of an anesthetic drug called ketamine. Their study, published recently in the Journal of Neuroscience, reveals the importance of a specific type of connection between brain cells and may also explain ketamine’s promise as a treatment for depression.

Much like the sound of a bark would make the listener expect to see a dog, the scientists taught volunteers to associate each series of three-syllable nonsense words with a picture from an assortment of three unique animal-like shapes called greebles. But the researchers skewed the predictive qualities of the sounds by making a greeble follow its matched sound 85 percent of the time, 50 percent of the time or 33 percent of the time.

“The stronger our listeners understood a sound was predictive of a certain shape, the quicker they could tell us if the shape we showed them matched the sound they’d just heard,” Saalmann says.

That’s because the most predictive sounds caused a flash of recognition in the form of a spike of activity in the higher-order regions in the front of the brain, followed by a signal — a kind of internal heads-up — sent down connected brain cells to the parts of the brain that directly take in sensory information.

That is, until the study subjects received a small dose of ketamine.

“The drug blocked that whole set of processes,” says graduate student Sounak Mohanta, “and slowed the subjects’ reactions until they were all relatively equal.”

Ketamine interfered with a specific communications channel by blocking NDMA receptors, a type of chemical connection between brain cells common on the neurons along the important pathways from the frontal lobe to sensory centers.

“The priming signal is lost. The brain no longer benefits from the top-down predictions, and errors happen,” says Saalmann.

This could actually benefit people with disorders, including depression and schizophrenia, in which the brain makes unnecessarily dire predictions. By interrupting that process, ketamine could keep people from anticipating the worst or hallucinating things that aren’t there. Already, ketamine has been shown to relieve depression-like symptoms in animal and human studies, and is being used for clinical studies of depression.

“Blocking the negative predictions that are prominent in depressed patients could be how ketamine helps,” Saalmann says. in the College of Agricultural and Life Sciences (CALS).

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