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What exactly happens in a brain when it is hit by a hallucinogen? Many drugs have effects that are an obvious extension of our normal body processes; they elevate mood, dull pain or boost our energy. But hallucinogens are notable for giving their users experiences that are anything but normal.

Now a team of Swiss researchers has used MRI imaging to monitor the brain as it is under the influence of acid. And their results support the idea that hallucinogens cause the breakdown of the system that helps the brain keep track of which information comes from the real world and which is generated by the brain itself.

Cortex overload

The brain receives a steady stream of information, some from the outside world, some from the body, and some generated by internal thought processes. Your brain essentially has to decide which of them to take seriously and raise to the level of consciousness, which ones to subconsciously control and which to throw away. Hallucinations, whether due to drugs or mental disorders, seem to involve a breakdown in this information processing.

We have an idea of ​​the different brain structures that are responsible for this processing. The cerebral cortex, for example, appears to be of crucial importance for consciousness, perception and attention. The thalamus also appears to be involved in consciousness, helping to relay sensory signals to other parts of the brain. Based on this and additional research, neuroscientists have proposed that the thalamus acts as a gatekeeper for sensory information flowing into the cortex.

In this model, hallucinogens suppress this gatekeeper function. As a result, the cortex becomes flooded with information and begins to lose track of information, leading to a flood of intense sensations and other cognitive distortions. The idea matches a lot of data we have, but it’s an extremely difficult idea to test. After all, people who use hallucinogens aren’t a reliable witness to anything, let alone their internal brain state.

To answer this question, the researchers behind the new work got their hands on a healthy supply of LSD and an MRI machine. These were combined with a relatively recently developed technique called dynamic causal modelling.

Functional meets causal

Normally, functional MRI (fMRI) imaging involves someone performing a task and then comparing the brain activity during the task with the resting activity. This method is great if you want to isolate a specific process, but it’s not particularly useful if you want to identify global changes in brain activity, such as those caused by LSD.

In this work, however, the researchers focused on the activity of the brain in two resting states: with and without acid. Even when we seem to be doing nothing, our brains experience waves of activity. Some brain regions signal independently, while others have linked activity — firing one region activates the other. Because so much happens in the brain, it’s hard to tell these situations apart.

That’s where dynamic causal modeling comes in. It involves researchers creating a predictive model and then running an algorithm to see if real-world data can fit into the model by adjusting the strength of the connections within it. Although it’s a complicated process, you can think of it as a way to check if the firing we see during normal brain activity matches the connections we think are present in the brain.

To make the comparison, the researchers used three different conditions: a group of control subjects, a group that had taken LSD and a group that took both LSD and a second drug. LSD, it turns out, binds to many proteins in the brain, including multiple receptors for serotonin and dopamine. The additional drug in these experiments, called Ketanserin, blocks only one of the serotonin receptors. But that’s enough to block most subjective experiences of taking acid. So while we can expect that LSD changes many activities that are not relevant to the hallucinogenic effects, the combination of the two drugs should help us determine which of these changes is most relevant to the problem at hand.

The researchers’ model tests identified a number of LSD-induced changes that are not altered by Ketanserin, suggesting they are not central to the hallucinations. And it identified another set of compounds that turned out to be crucial for the hallucinogenic effects.

Gatekeeper or organizer?

In general, these effects were consistent with the model, in which the thalamus acts as a gatekeeper for the cerebral cortex. But instead of a general flooding of the cortex, they found that a limited number of specific regions saw increased activity. This suggests that the states induced by hallucinogens are different from states such as anesthesia and sleep, which lead to widespread changes in the cortex. To some extent this is a “duh!” since you can have conversations with people on acid. But it’s an important finding for future studies that want to further tease how hallucinogens work.

Of course, LSD isn’t the only hallucinogen out there; other studies have looked at ayahuasca and psilocybin. These results are generally consistent with the results reported here, but also suggest that psychedelic drugs may simply lead to a disorganization of signaling in the brain. And at our current level of understanding it is not possible to distinguish between these two models.

Which of course means that the people in Zurich will be lining up extra volunteers to take some acid and find out if it’s fun to sit in an MRI tube.

PNAS2019. DOI: 10.1073/pnas.1815129116 (About DOIs).

By akfire1

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