Why don’t we hallucinate more often?

It’s a question they might have asked for different reasons in the ’60s, but neuroscientists from Stanford University in the US are wondering why we aren’t hallucinating all the time.

If we’re wired anything like mice, they say, it should be quite easy to do.

Karl Deisseroth and colleagues found that they only needed to stimulate a surprisingly small number of nerve cells, or neurons, in the visual cortex of mice to induce an illusory image in their minds, leading them to behave in a particular way.

And that’s worth knowing, they say, because it could help provide a better understanding of natural information processing in the brain, and of psychiatric disorders such as schizophrenia.

“Back in 2012, we had described the ability to control the activity of individually selected neurons in an awake, alert animal,” Deisseroth says.

“Now, for the first time, we’ve been able to advance this capability to control multiple individually specified cells at once, and make an animal perceive something specific that in fact is not really there – and behave accordingly.” 

The findings are presented in a paper published in the journal Science.

Deisseroth is a leading exponent of optogenetics, a technology that allows researchers to stimulate particular neurons in freely moving animals with pulses of light, and to observe the resulting effects on the animals’ brain function and behaviour. He and three colleagues were honoured for their pioneering work this week. 

In their latest study, he and his Stanford team used a specially-developed device to project holograms – three-dimensional configurations of targeted photons – onto, and into, a mouse’s visual cortex. 

As they describe it, these photons would land at precise spots along specific neurons, and they could then monitor the resulting activity of nearly all individual neurons in two distinct layers of the cerebral cortex containing several thousand neurons.

When mice were shown random series of horizontal and vertical bars displayed on a screen, the researchers recorded which neurons in the exposed visual cortex were preferentially activated by one or the other orientation. From these results, they were able to identify dispersed populations of individual neurons that were “tuned” to either horizontal or vertical visual displays.

They were then able to “play back” these recordings in the form of holograms that produced spots of infrared light on just neurons that were responsive to horizontal, or to vertical, bars. 

The resulting downstream neuronal activity, even at locations relatively far from the stimulated neurons, was quite similar to that observed when the natural stimulus – a black horizontal or vertical bar on a white background – was displayed on the screen.

Then, the scientists say, they trained the mice to lick the end of a nearby tube for water when they saw a vertical bar but not when they saw a horizontal one or saw neither. As the mice’s ability to discriminate between horizontal and vertical bars improved, they reduced the black-white contrast to make the task progressively harder. 

The mice’s performance perked up if the visual displays were supplemented with simultaneous optogenetic stimulation – but only when the stimulation was consistent with the visual stimulation; for example, a vertical bar display plus stimulation of neurons previously identified as likely to fire in response to vertically oriented bars.

Once the mice had become adept at discriminating between horizontal and vertical bars, the researchers were able to induce tube-licking behaviour simply by projecting the “vertical” holographic program onto the mice’s visual cortex. But the mice wouldn’t lick the tube if the “horizontal” program was projected instead.

“Not only is the animal doing the same thing, but the brain is, too,” Deisseroth says. “So we know we’re either recreating the natural perception or creating something a whole lot like it.”

In early experiments, the team had identified neurons as being tuned to either a horizontal or a vertical orientation but couldn’t stimulate each of them optogenetically. Once the mice were trained, however, optogenetic stimulation of just 20 or even fewer neurons was enough to get mice to respond with appropriate licking or non-licking behaviour.

“It’s quite remarkable how few neurons you need to specifically stimulate in an animal to generate a perception,” Deisseroth says.

“A mouse brain has millions of neurons; a human brain has many billions,” he adds. 

“If just 20 or so can create a perception, then why are we not hallucinating all the time, due to spurious random activity? Our study shows that the mammalian cortex is somehow poised to be responsive to an amazingly low number of cells without causing spurious perceptions in response to noise.”