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Hallucinations are spooky and  fortunately  fairly rare  But  a new study suggests  the real question isn t so much why some people occasionally experience them  It s why all of us aren t hallucinating all the time

In the study  Stanford University School of Medicine neuroscientists stimulated nerve cells in the visual cortex of mice to induce an illusory image in the animals  minds  The scientists needed to stimulate a surprisingly small number of nerve cells  or neurons  in order to generate the perception  which caused the mice to behave in a particular way

 Back in 2012  we had described the ability to control the activity of individually selected neurons in an awake  alert animal   said Karl Deisseroth  MD  PhD  professor of bioengineering and of psychiatry and behavioral sciences   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 study  to be published online July 18 in Science  holds implications for obtaining a better understanding of natural information processing in the brain  as well as psychiatric disorders such as schizophrenia  and points to the possibility of designing neural prosthetic devices with single cell resolution

Deisseroth is the study s senior author  Lead authorship is shared by staff scientists James Marshel  PhD  and Sean Quirin  PhD  graduate student Yoon Seok Kim  and postdoctoral scholar Timothy Machado  PhD

Using optogenetics

Deisseroth  who is a Howard Hughes Medical Institute investigator and holds the D  H  Chen Professorship  pioneered optogenetics  a technology enabling 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 behavior

In the new study  Deisseroth and his colleagues inserted a combination of two genes into large numbers of neurons in the visual cortex of lab mice  One gene encoded a light sensitive protein that caused the neuron to fire in response to a pulse of laser light of a narrowly defined color    in this case  in the infrared spectrum  The other gene encoded a fluorescent protein that glowed green whenever the neuron was active

The scientists created cranial windows in the mice by removing a portion of the animals  skulls to expose part of the visual cortex  which in both mice and humans is responsible for processing information relayed from the retina  The investigators protected this exposed area with a clear glass covering  They could then use a device they developed for the purpose of the study to project holograms    three dimensional configurations of targeted photons    onto  and into  the visual cortex  These photons would land at precise spots along specific neurons  The researchers could monitor the resulting activity of nearly all individual neurons in two distinct layers of the cerebral cortex spanning about 1 square millimeter and containing on the order of several thousand neurons

With their heads fixed in a comfortable position  the mice were shown random series of horizontal and vertical bars displayed on a screen  The researchers observed and recorded which neurons in the exposed visual cortex were preferentially activated by one or the other orientation  From these results  the scientists 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

The scientists 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  Over the course of several days  as the animals  ability to discriminate between horizontal and vertical bars improved  the scientists gradually reduced the black white contrast to make the task progressively harder  They found that the mice s performance perked up if the scientists supplemented the visual displays with simultaneous optogenetic stimulation  For example  if an animal s performance deteriorated as a result of a lowered contrast  the investigators could boost its discrimination powers by stimulating neurons previously identified as preferentially disposed to fire in response to a horizontal or vertical bar

This boost occurred only when the optogenetic 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

Hallucinating mice

Once the mice had become adept at discriminating between horizontal and vertical bars  the scientists were able to induce tube licking behavior in the mice 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 said   So we know we re either recreating the natural perception or creating something a whole lot like it 

In their early experiments  the scientists had identified numerous neurons as being tuned to either a horizontal or a vertical orientation  but they hadn t yet directly stimulated each of those particular neurons optogenetically  Once the mice were trained  optogenetic stimulation of small numbers of these neurons was enough to get mice to respond with appropriate licking or nonlicking behavior

The researchers were surprised to find that optogenetically stimulating about 20 neurons    or fewer in some cases    selected only for being responsive to the right orientation  could produce the same neuronal activity and animal behavior that displaying the vertical or horizontal bar did

 It s quite remarkable how few neurons you need to specifically stimulate in an animal to generate a perception   Deisseroth said

 A mouse brain has millions of neurons  a human brain has many billions   he said   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 

Deisseroth is a member of Stanford Bio X and of the Wu Tsai Neurosciences Institute at Stanford

Stanford s Office of Technology Licensing has filed a patent application for intellectual property associated with the work

The work was funded by the Defense Advanced Research Projects Agency  HHMI  the National Institutes of Health (grants R01MH075957 and P50DA042012)  the Simons Foundation  the Wiegers Family Fund  the Nancy and James Grosfeld Foundation  the Sam and Betsy Reeves Fund  the H L  Snyder Foundation  the Burroughs Wellcome Foundation  the McKnight Foundation  the James S  McDonnell Foundation and the Swartz Foundation