Scientists have discovered the hidden brain flaw that causes people with schizophrenia to lose touch with reality – and say it could open the door to better treatments.
Researchers at MIT have discovered a faulty circuit deep within the brain that prevents a person from updating their beliefs when the world around them changes.
The findings could help explain why some sufferers become ‘detached’ or trapped in false ideas and delusions even when faced with clear evidence that those beliefs are wrong.
Experts say the findings shed new light on one of psychiatry’s most perplexing illnesses, which affects up to 3.7 million Americans.
Schizophrenia is a severe mental health disorder that can cause psychosis, hallucinations, paranoia, confused thinking and a reduced ability to function day to day.
Patients may hear voices, believe strangers are watching them, or become convinced ordinary events carry secret personal meaning.
In the hunt to find out why, the MIT researchers focused on a gene called GRIN2A, which helps build part of the NMDA receptor – a protein on brain cells involved in learning, memory and flexible thinking.
A person without schizophrenia would see the traffic, realize ‘Main Street is no longer fast,’ and immediately turn onto a side street. No second thoughts. For many people with schizophrenia, that simple mental update breaks. They stick with Main Street.
Schizophrenia is a serious mental illness marked by hallucinations, paranoia, scrambled thinking and a diminished ability to manage daily life (stock)
They trust their old belief more than the new information right in front of them, even when it clearly isn’t working. Their decision becomes detached from reality.
Researchers at MIT have now identified the grin2a mutation as the reason.
It provides instructions for building part of the NMDA receptor, a protein on the surface of brain cells that is critical for learning, memory and adaptation.
When grin2a is mutated, that receptor doesn’t work properly. Scientists call this ‘NMDA receptor hypofunction,’ or reduced function.
This discovery fits a long-standing theory of schizophrenia called the glutamate hypothesis — the idea that problems with glutamate signaling, a key brain chemical, are a root cause of the disorder.
The genetic link to the disorder is strong. In the general population, about 1 in 100 people develop schizophrenia. But if a parent or sibling has it, the risk jumps to 1 in 10. For identical twins, it is 1 in 2.
Grin2a, one of the many genes linked to schizophrenia, makes people more than 20 times more likely to develop schizophrenia.
To understand how this single genetic error causes real-world problems, researchers used CRISPR gene editing to create mice carrying the exact same grin2a mutation found in human patients.
Mice with the grin2a mutation (mutant) made far less efficient (written here as optimal) choices than healthy mice, scoring significantly lower on a measure of optimal decision-making
Then, they designed a test. Mice were given a choice between two levers. One lever gave a high reward, three drops of milk, but required more and more presses over time. The other lever gave a low reward, one drop of milk, but always required exactly six presses.
Healthy mice figured out the pattern quickly. When the high-reward lever became too much work, they switched to the low-reward lever and stayed there.
The mutant mice kept pressing the high-reward lever long after it became no longer worth it.
They struggled to update their strategy based on new information, just like schizophrenia patients who cannot let go of an old belief even when the world has changed around them.
Next, the researchers needed to find where in the brain this was going wrong.
They used a technique called optogenetics, which uses light to control genetically modified neurons.
They silenced a brain region called the mediodorsal thalamus in healthy mice. Immediately, those mice started behaving just like the mutants. They made the same poor choices. They got stuck.
Then came the critical test.
With the laser off (gray line), healthy mice quickly abandoned a worsening choice. With the laser on (green line), silencing their mediodorsal thalamus, they kept making the same poor choice, just like mice with a schizophrenia-linked mutation
The researchers activated the same brain region in the mutant mice using a brief pulse of blue light and saw a dramatic result. The mutant mice’s behavior improved; they switched levers at the right time and made optimal choices.
By turning a single brain circuit on and off with light, the researchers proved that the mediodorsal thalamus is the source of the problem. Silencing it caused the deficit. Activating it reversed it.
‘We are quite confident this circuit is one of the mechanisms that contributes to the cognitive impairment that is a major part of the pathology of schizophrenia,’ said Dr. Guoping Feng, a neuroscientist at MIT and senior author of the study.
The latest study, published in Nature Neuroscience, does not offer an immediate cure, and optogenetics — using lasers to control brain cells — is a laboratory tool, not a human therapy.
But by identifying the mediodorsal thalamus as a key node in the broken circuit, researchers have given drug developers a specific target to aim for.
Dr Tingting Zhou, a co-author of the study, said: ‘Our brain can form a prior belief of reality. When sensory input comes in, a neurotypical brain uses that new input to update the prior belief. That allows us to generate a new belief close to what reality is.
‘What happens in schizophrenia patients is that they weigh too heavily on the prior belief. They don’t use as much current input, so the new belief becomes detached from reality.’
That detachment does not come on in full force all at once.
At first, the changes are small. A person might start doubting things they once knew to be true, such as a friend’s loyalty or the meaning of a random comment from a classmate.
Soon, internal thoughts and external reality begin to blur. Early signs typically include withdrawing from social life, anxiety, neglecting personal hygiene, reducing motivation and isolating oneself.
Someone may begin to believe they are in an alternate universe or that others are inserting thoughts or voices into their mind. Over time, they stop trusting what they see and hear.
Instead, they rely on ideas that have no connection to the outside world.
A passing car is not just a car; it is following them. A news anchor is not reading the news; they are sending a secret message.
The person does not choose to believe these things, but their brain has lost the ability to update its understanding of reality.
