Scientists discover brain flaw that may explain why schizophrenia sufferers lose touch with reality

Scientists have discovered a hidden brain defect that causes people with schizophrenia to lose touch with reality, and they say it could open the door to better treatments.

Researchers at MIT have discovered a faulty circuit deep in the brain that prevents a person from updating their beliefs when the world around them changes.

The findings may help explain why some patients remain ‘unattached’ or trapped in false ideas and delusions, even when faced with clear evidence that these beliefs are false.

Experts say the findings shed new light on one of psychiatry’s most puzzling illnesses, affecting up to 3.7 million Americans.

Schizophrenia is a serious mental health disorder that can cause psychosis, hallucinations, paranoia, confusion, and decreased daily functioning.

Patients may hear voices, believe strangers are watching them, or believe that ordinary events carry hidden personal meaning.

In their quest to find out why, MIT researchers focused on a gene called GRIN2A, which helps form part of the NMDA receptor, a protein on brain cells involved in learning, memory and flexible thinking.

A person without schizophrenia sees the traffic, realizes that ‘Main Street is not fast anymore’ and immediately turns into a side street. No need for a second thought. For most people with schizophrenia, this simple mental updating is impaired. They stay true to Main Street.

They rely on their old beliefs rather than the new information in front of them, even when it clearly doesn’t work. Their decisions are disconnected from reality.

Researchers at MIT have now identified the grin2a mutation as the cause.

It provides instructions for creating 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, this receptor does not work properly. Scientists call this ‘NMDA receptor hypofunction’ or reduced function.

This discovery fits with a long-standing theory of schizophrenia called the glutamate hypothesis; This theory fits with the idea that problems with glutamate signaling, an important brain chemical, are the root cause of the disorder.

The genetic link to the disorder is strong. About 1 in 100 people in the general population develop schizophrenia. However, if a parent or sibling has this disease, the risk increases to 1 in 10. In identical twins, this rate is 1 in 2.

Grin2a, one of 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 same grin2a mutation found in human patients.

Mice with the Grin2a mutation (mutant) made significantly less efficient (here spelled optimal) choices than healthy mice and scored significantly lower on a measure of optimal decision-making.

Then they designed a test. Mice were given the choice between two levers. A lever offered a high reward, such as three drops of milk, but needed to be pressed more and more over time. The other lever gave a low reward, namely a drop of milk, but it always had to be pressed exactly six times.

Healthy mice quickly understood the model. When the high reward arm started doing too much work, they moved to the low reward arm and stayed there.

The mutant mice continued to press the high reward lever even after it was no longer worth it.

Just like schizophrenia patients who cannot give up an old belief even as the world around them changes, they struggled to update their strategies based on new information.

Then researchers needed to find where in the brain this went 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. Suddenly, these mice started acting just like mutants. They made the same bad choices. They are stuck.

Then came the critical test.

With the laser off (gray line), healthy mice gave up a rapidly worsening choice. With the laser on (green line), they continued to make the same bad choice by silencing their mediodorsal thalamus, just like mice with the schizophrenia-related mutation.

The researchers activated the same brain region in mutant mice using a brief pulse of blue light and saw a dramatic result. The mutant mice’s behavior improved; They changed arms at the right time and made the most appropriate choices.

By turning a single brain circuit on and off with light, the researchers proved that the source of the problem was the mediodorsal thalamus. Silencing him resulted in the exposure. Once activated, the situation was reversed.

MIT neuroscientist and senior author of the study Dr. ‘We are quite confident that this circuit is one of the mechanisms that contributes to the cognitive impairment that is an important part of the pathology of schizophrenia,’ said Guoping Feng.

The latest study was published on: Nature NeuroscienceIt does not offer an immediate cure, and optogenetics (the use of 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 defective circuit, the researchers gave drug developers a specific target to target.

One of the authors of the study, Dr. Tingting Zhou said: ‘Our brain can form a preconceived belief in reality. When sensory input arrives, a neurotypical brain uses this new input to update the previous belief. This allows us to generate a new belief that is close to what reality is.

‘What happens with schizophrenic patients is that they place too much weight on previous beliefs. ‘They don’t use a lot of current input, so the new belief becomes disconnected from reality.’

This rupture does not emerge with full force all at once.

At first the changes are small. A person may begin to doubt things they once knew to be true, such as the loyalty of a friend or the meaning of a random comment from a classmate.

Soon inner thoughts and outer reality begin to blur. Early symptoms often include social withdrawal, anxiety, neglect of personal hygiene, decreased motivation and self-isolation.

Someone may begin to believe that 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; follows them. A news anchor doesn’t read the news; They are sending a secret message.

The person does not choose to believe them, but their brain has lost the ability to update its understanding of reality.