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Sheep-on-ketamine study reveals what happens when you fall into a "k-hole"

The brain isn't dead or damaged, but the lights are out.

Humans who descend into a "k-hole" describe an intense state of oblivion that’s not unlike a near-death experience. It's what happens when one takes a high enough dose of ketamine that they feel what's described as a separation of mind and body.

Scientifically speaking, we didn’t know much about why ketamine causes that to happen. But thanks to some sheep in England who accidentally fell into a k-hole, researchers are very close to understanding.

A general anesthetic once popular as a rave drug, ketamine has gained traction as a novel tool for treating depression. It's known for its fast-acting soothing of suicidal thoughts, and the creation of new connections in the brain that might sustain anti-depressant effects — in 2019, a ketamine-based nasal spray became approved to alleviate treatment-resistant depression. It's far from a perfect solution, but new research has also shown it also has the potential for combating alcohol abuse.

A study published Thursday in Scientific Reports shows that ketamine can also substantially change the way brain waves work.

This helps explain the drug's dissociative effects, including the experience of falling into a k-hole. When sheep were given 24mg/kg of ketamine, the electrical activity in the cerebral cortex completely stopped. (The study reports that this is on the high end of the anesthetic use range. Dosages for recreational ketamine vary).

Jenny Morton, the lead study author and a professor of neurobiology at The University of Cambridge, tells Inverse that there probably was some brain activity happening in the deep brain — the sheep were still breathing, after all. But the cerebral cortex, which is “usually very active, had just gone very quiet.”

“The activity in the cortex in some of the sheep stops completely for a short time. But the brain is NOT dead or damaged,” she explained by email.

A few minutes later, the sheep brains were functioning normally again, Morton added. The study suggests that this strange moment — when activity seemed to cease — might represent what happens in the brain after a k-hole fall.

The brain on ketamine – The study was actually never intended to plumb the neurological depths of the k-hole. It was designed to be an investigation of therapeutic drugs, like ketamine, on the brains of those with Huntington’s disease. Sheep are often used as models of Huntington’s disease in research. That drug just happened to be ketamine in this case.

An "EEG hole" or, likely, a K-hole, as seen in one sheep in the experiment. Scientific Reports

Over the course of several months, the researchers gave 12 sheep escalating doses of the drug from 0.5 mg/kg to 24 mg/kg. They also took EEG readings of their cerebral cortices to see how the brain's electrical activity matches up with their drug experiences.

At the lower doses, they found that the brain goes through three phases while on ketamine. Sheep entered the first phase “shortly” after receiving ketamine, the paper notes. They lost the ability to move, but their eyes stayed open (they could also blink).

Then, the sheep entered the second phase: They still couldn't move but were able to “respond” to touch or movements in front of them. In the third phase, they were conscious and alert with “awake levels” of EEG activity, though they didn't move around.

However, the crucial patterns of brain activity were seen during the second phase.

When we’re awake, the activity in the cerebral cortex usually covers a wide band of frequencies or “waves” says Morton. You can think of that as a conversation in a busy restaurant. Things seem chaotic while lots of information is being exchanged during conversations at different tables.

During the second phase of a ketamine high, the team observed oscillations between lower frequency theta waves and higher frequency gamma waves. That’s like having groups of tables performing a call-and-response to one another in unison, Morton says. There's a lot of talking, but not a lot of information being exchanged.

This “oscillation of oscillations,” or pattern of brain activity, is probably responsible for the dissociative experiences of ketamine, even before falling into a k-hole. The brain is processing reality and exchanging information, in a uniform but very different way.

In turn, the six sheep who received the highest doses of ketamine had very different patterns of brain activity shortly after getting dosed. In five of the sheep, after two minutes, their brain activity seemed to shut off."

“The cortex is the part of the brain that is essential for thinking and decision making. We speculate that if ketamine causes a cessation of EEG activity in the cortex in humans, that this feeling of insensibility would result,” says Morton.

Sheep brains and human brains are far from perfect parallels, and the team was only imaging the cerebral cortex. There could be far more complex processes that underpin the experience of ketamine.

We already know that ketamine works by inhibiting the action NMDA receptors in the brain, which is one way it causes a dissociative state. That’s one reason it works as anesthesia, but whether that’s the mechanism that causes its fast-acting effects on depression is currently out for debate.

Morton's work suggests that this oscillating behavior between two brain waves continues even after the sheep recovered from sedation (or at least appeared to). That adds yet another layer of complexity, suggesting that the drug's effects could persist in the brain after sheep appear to wake up.

This study is also another demonstration that we still don’t know everything about how ketamine works — especially when it causes the cerebral cortex to go quiet.

Abstract: Ketamine is a valuable anesthetic and analgesic that in recent years has gained notoriety as a recreational drug. Recently, ketamine has also been proposed as a novel treatment for depression and post-traumatic stress disorder. Beyond its anesthetic actions, however, the effects of ketamine on brain activity have rarely been probed. Here we examined the cortical electroencephalography (eeG) response to ketamine of 12 sheep. Following ketamine administration EEG changes were immediate and widespread, affecting the full extent of the EEG frequency spectrum measured (0–125 Hz). After recovery from sedation during which low frequency activity dominated, the EEG was characterized by short periods (2–3 s) of alternating low (<14 Hz) and high (>35 Hz) frequency oscillation. This alternating eeG rhythm phase is likely to underlie the dissociative actions of ketamine, since it is during this phase that ketamine users report hallucinations. At the highest intravenous dose used (24 mg/kg), in 5/6 sheep we observed a novel effect of ketamine, namely the complete cessation of cortical eeG activity. this persisted for up to several minutes, after which cortical activity resumed. this phenomenon is likely to explain the ‘k-hole’, a state of oblivion likened to a near death experience and keenly sought by ketamine abusers.
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