People under the influence of hallucinogenic drugs like LSD often experience vivid visual hallucinations. But exactly what is happening within the brain to induce such a state remains a mystery. According to a new paper in Cell Reports, experiments with mice under the influence of a hallucinogenic drug showed evidence that the hallucinations may be triggered by reduced signaling between neurons in the visual cortex, along with changes in the timing at which they fire.

This might seem counterintuitive, according to co-author Cris Niell, a neuroscientist at the University of Oregon. "You might expect visual hallucinations would result from neurons in the brain firing like crazy or by mismatched signals," he said. "We were surprised to find that a hallucinogenic drug instead led to a reduction of activity in the visual cortex. But in the context of visual processing, it made sense."

In short, the brain may just be over-interpreting a lack of information. When we dream, for instance, there are no visual signals entering the brain, and yet the brain still creates visual patterns.

His team's findings may help further the potential of such drugs to treat anxiety, depression, or schizophrenia (which often produces aural and/or visual hallucinations). Albert Hofmann first synthesized LSD in 1938 while working for the pharmaceutical giant Sandoz, and it was originally used as a treatment for anxiety and depression under the trade name Delysid. More than 1,000 research papers were published between 1950 and 1965, until the 1970 Controlled Substance Act made it well-nigh impossible to get federal funding or the drugs needed for trial studies. LSD-related research pretty much stopped after that, but over the last 15 years or so, hallucinogenic drugs have been making a comeback in research circles.

Altering the brain’s receiver

After experiencing LSD's hallucinatory effects on the infamous "Bicycle Day" in April 1943, Hofmann speculated that the drug biochemically altered the brain's "receiver," tuning it to a different wavelength. In his book, The Doors of Perception, Aldous Huxley speculated that LSD works by counteracting what he called a "reducing valve" in the brain that typically limits our perceptions. That means humans tripping on acid get more sensory input than usual due to a decrease in brain activity. And several prior brain-imaging studies involving humans have shown that psychedelics disrupt normal brain activity and boost the random firing of neurons in the visual cortex.

For instance, a 2012 study out of neuropsychopharmacologist David Nutt's Imperial College laboratory in England scanned the brains of 30 subjects (all experienced users of psychedelics) while under the influence of psilocybin—aka magic mushrooms. The lab then compared them to scans taken after the subjects ingested a salt water placebo. (Side note: Nutt was infamously fired in 2009 from his post as Britain's chief drug advisor for arguing that psychedelic drugs had been unfairly stigmatized.)

Nutt and his colleagues found the overall brain activity dropped in the so-called "default mode," a collection of highly interconnected neuronal networks that typically fire together when the brain is at rest. Psilocybin disrupted that synchronization, which could cause the dissociative aspects—the oft-reported sense of a disintegrating sense of self or ego—of hallucinogenic drugs.

In 2016, Nutt et al. published the results of a second fMRI study, this time with subjects under the influence of LSD, compared with a placebo. Once again, there was less synchronization (overall brain activity) among neurons in the default mode. But they also found that certain disparate regions of the brain that normally didn't communicate with each other did so under the influence of LSD, particularly the visual cortex. This could explain the vividly intricate hallucinations experienced by people tripping on acid. The effect appears to be separate from that of ego dissolution, however; it's possible to experience one without the other.

Yet another study the following year in Scientific Reports found a sudden increase in randomness in brain activity in subjects under the influence of psychedelic drugs. This is possible evidence for a heightened state of consciousness commonly associated with psychedelics.

"People tend to associate phrases like 'a higher state of consciousness' with hippy speak and mystical nonsense," co-author Robin Carhart-Harris of Imperial College told The Guardian. "This is potentially the beginning of the demystification, showing its physiological and biological underpinnings. Maybe this is a neural signature of the mind opening."

“[It’s] like listening to the roar of the crowd at a stadium, versus being able to listen in on individual conversations.”

Earlier this year, a team of Swiss researchers used MRI imaging to follow the brain as it's under the influence of acid. The researchers' results support the idea that hallucinogens cause the breakdown of the system that helps the brain keep track of which information is coming from the real world and which is generated by the brain itself. As Ars' John Timmer reported in February, "Instead of a general flooding of the cortex, they found that a limited number of specific regions saw increased activity. This suggests the states induced by hallucinogens are distinct from states like anesthesia and sleep, which lead to widespread changes in the cortex."

Mice on acid

Nutt et al.'s research was certainly on Niell's mind when he embarked on his experiments with mice, although the focus of his research is primarily on how visual perception works in general. He realized studying hallucinations, where visual perception is disrupted, would be a good exploratory mechanism, especially if he could measure what was happening at the scale of individual neurons.

The human fMRI studies on drug-induced hallucinations measure ongoing brain activity, while Niell's mouse study measures how the mouse brains respond to specific sensory stimuli, in this case visual inputs. Furthermore, fMRI measures the activity of millions of neurons summed together, and it's technically measuring changes in blood flow—more of an indirect measure of brain activity in humans. By contrast, Niell's group directly measured the activity of hundreds of individual neurons simultaneously.

"This is like the difference between listening to the roar of the crowd at a stadium, versus being able to listen in on individual conversations within the crowd," said Niell.

Because LSD and similar hallucinogens are classified as Schedule I substances by the US Drug Enforcement Agency and are hence difficult to obtain, even for laboratory use, Niell and his colleagues used a chemically similar drug called DOI (4-iodo-2,5-dimethoxyphenyl isopropylamine). This targets the same serotonin 2A receptors as LSD and psilocybin.

Michaiel et al./Cell Reports

Michaiel et al./Cell Reports

YouTube/Disney

How could they tell if the mice were hallucinating? Unlike humans, mice can't describe their experiences while tripping. "We have indirect ways of probing what they're seeing," said Niell. Those ways usually involved having the mice run toward a vertical line or a horizontal line in exchange for a reward (e.g., food). Mice under the influence may twitch their heads or move their paws in unusual ways.

Then the researchers plopped the drugged mice onto a little running wheel and showed them various images on a computer screen, monitoring their brain response with both calcium imaging and single-unit electrophysiology. That way, "You know not just what each individual neuron is saying, but how its interactions are changing," said Niell. And what they found was that the usual burst of activity in response to a visual stimulus is suppressed, altering the timing of the information, which in turn could affect how it travels to other regions of the brain.

Since there was no change in the signals being sent to the visual cortex, the team concluded that hallucinations might be related to how the sensory information is being interpreted rather than by what's coming in. "Understanding what's happening in the world is a balance of taking in information and your interpretation of that information," said Niell. "If you're putting less weight on what's going on around you but then over-interpreting it, that could lead to hallucinations."

DOI: Cell Reports, 2019. 10.1016/j.celrep.2019.02.104 (About DOIs).