Key Brain Systems Implicated in Psychosis

Summary: Researchers provide new information on the brain mechanisms behind psychosis. Research has identified dysfunctions in two critical brain systems: the “filter” and the “predictor” in people with psychosis.

These systems, which help direct attention and anticipate rewards, are impaired, leading to symptoms such as hallucinations and delusions. By studying young individuals with 22q11.2 deletion syndrome, a condition with a high risk of psychosis, researchers are providing a clearer picture of how these dysfunctions occur, potentially guiding future treatments and prevention strategies.

Highlights:

1. The study focuses on individuals with 22q11.2 deletion syndrome, linking their brain patterns to common symptoms of psychosis.
2. It reveals that dysfunctions in the brain’s reward filtering and prediction systems are at the heart of psychosis, affecting the way reality is perceived.
3. The research used advanced imaging and machine learning to identify and confirm these dysfunctions, providing potential new targets for therapeutic interventions.

Source: Stanford

In the brains of people with psychosis, two key systems malfunction: a “filter” that directs attention to important external events and internal thoughts, and a “predictor” composed of pathways that anticipate rewards.

The dysfunction of these systems makes it difficult to know reality, manifesting itself in hallucinations and delusions.

The results come from a study led by Stanford Medicine, published April 11 in Molecular Psychiatry, which used brain scan data from children, adolescents and young adults with psychosis. The results confirm an existing theory about how breaks with reality occur.

“This work provides a good model for understanding the development and progression of schizophrenia, which is a challenging problem,” said lead author Kaustubh Supekar, Ph.D., clinical associate professor of psychiatry and behavioral sciences.

The findings, observed in individuals with a rare genetic disorder called 22q11.2 deletion syndrome and psychosis as well as those with psychosis of unknown origin, advance scientists’ understanding of the underlying brain mechanisms and theoretical frameworks related to psychosis.

During psychosis, patients experience hallucinations, such as hearing voices, and have delusional beliefs, such as thinking that people who are not real exist. Psychosis can occur on its own and is a feature of some serious mental illnesses, including bipolar disorder and schizophrenia.

Schizophrenia is also characterized by social withdrawal, disorganized thinking and speech, and reduced energy and motivation.

It is difficult to study how schizophrenia begins in the brain. This illness usually appears in adolescents or young adults, most of whom quickly begin taking antipsychotic medications to relieve their symptoms.

When researchers analyze brain scans of people with proven schizophrenia, they cannot distinguish the effects of the illness from those of medications. They also don’t know how schizophrenia changes the brain as the illness progresses.

To gain an early insight into the disease process, the Stanford Medicine team studied young people ages 6 to 39 with 22q11.2 deletion syndrome, a genetic disorder with a 30% risk of psychosis, schizophrenia or two.

Brain function in 22q11.2 patients with psychosis is similar to that of people with psychosis of unknown origin, they found. And these brain patterns matched what researchers had previously theorized would generate symptoms of psychosis.

“The brain patterns we identified support our theoretical models of how cognitive control systems malfunction in psychosis,” said study lead author Vinod Menon, Ph.D., Rachael L. and Walter F. Nichols, MD, professor; professor of psychiatry and behavioral sciences; and director of the Stanford Cognitive and Systems Neuroscience Laboratory.

Thoughts that aren’t tied to reality can tap into the brain’s cognitive control networks, he said. “This process derails the normal functioning of cognitive control, allowing intrusive thoughts to dominate, resulting in symptoms that we recognize as psychosis. »

Brain sorting

Normally, the brain’s cognitive filtering system, called the salience network, works behind the scenes to selectively direct our attention to important internal thoughts and external events. With its help, we can reject irrational thoughts and unimportant events and focus on what is real and meaningful to us, such as paying attention to traffic to avoid a collision.

The ventral striatum, a small region of the brain, and associated brain pathways driven by dopamine, play an important role in predicting what will be rewarding or important.

For the study, researchers gathered as much functional brain MRI data as possible from young people with 22q11.2 deletion syndrome, totaling 101 individuals scanned at three different universities.

The study also included brain scans of several comparison groups without 22q11.2 deletion syndrome: 120 people with early idiopathic psychosis, 101 people with autism, 123 people with attention deficit disorder /hyperactivity and 411 healthy controls.

This genetic disease, characterized by the deletion of part of the 22nd chromosome, affects 1 in 2,000 to 4,000 people. In addition to the 30% risk of schizophrenia or psychosis, people with the syndrome can also suffer from autism. or attention deficit hyperactivity disorder, therefore these conditions were included in the comparison groups.

The researchers used a type of machine learning algorithm called a spatiotemporal deep neural network to characterize patterns of brain function in all patients with 22q11.2 deletion syndrome compared to healthy subjects.

With a cohort of patients whose brains were scanned at the University of California, Los Angeles, they developed an algorithmic model that distinguished brain scans of people with 22q11.2 deletion syndrome from those without it. .

The model predicted the syndrome with greater than 94% accuracy. They validated the model in additional groups of people with and without genetic syndrome who had received brain scans at UC Davis and the Pontificia Universidad Católica de Chile, showing that in these independent groups the model sorted brain scans with an accuracy of 84 to 90%.

The researchers then used the model to study which brain features play the greatest role in psychosis. Previous studies of psychosis have not yielded consistent results, likely because their sample sizes were too small.

By comparing brain scans of patients with 22q11.2 deletion syndrome who did and did not have psychosis, researchers showed that the brain areas contributing most to psychosis are the anterior insula (a key part of the salience network or “filter”) and the ventral striatum. (the “reward predictor”); this was true for different patient cohorts.

Comparing the brain features of people with 22q11.2 deletion syndrome and psychosis with those of people with psychosis of unknown origin, the model found significant overlap, indicating that these brain features are characteristic of psychosis in general .

A second mathematical model, trained to distinguish all subjects with 22q11.2 deletion syndrome and psychosis from those with the genetic syndrome but without psychosis, selected brain scans of people with idiopathic psychosis with an accuracy of 77.5 %, again confirming the idea that brain filtering and prediction centers are the key to psychosis.

In addition, this model was specific to psychosis: it did not make it possible to classify people with idiopathic autism or ADHD.

“It was very exciting to retrace our steps back to our original question: ‘What are the dysfunctional brain systems in schizophrenia?’ – and discover similar patterns in this context,” Menon said.

“At the neuronal level, the characteristics differentiating individuals with psychosis in 22q11.2 deletion syndrome mirror pathways we have identified in schizophrenia. This parallel strengthens our understanding of psychosis as a condition with identifiable and consistent brain signatures.

However, these brain signatures were not observed in people with the genetic syndrome but not psychosis, providing clues to future research directions, he added.

Treatment or prevention applications

As well as supporting the scientists’ theory of how psychosis occurs, the findings have implications for understanding the illness and potentially preventing it.

“One of my goals is to prevent or delay the development of schizophrenia,” Supekar said. The fact that the new findings agree with the team’s previous research on which brain centers contribute most to schizophrenia in adults suggests there might be a way to prevent it, he said.

“In schizophrenia, by the time of diagnosis, a lot of damage has already occurred in the brain and it can be very difficult to change the course of the illness.”

“What we found is that from the beginning, the functional interactions between brain regions within the same brain systems are abnormal,” he added. “Abnormalities don’t start when you’re in your 20s; they are obvious even when you are 7 or 8 years old.

Researchers plan to use existing treatments, such as transcranial magnetic stimulation or focused ultrasound, targeted to these brain centers in youth at risk for psychosis, such as those with 22q11.2 deletion syndrome or in both affected parents of schizophrenia, to see if they prevent or delay the onset of the illness or alleviate symptoms once they appear.

The findings also suggest that using functional MRI to monitor brain activity in key centers could help scientists study how existing antipsychotic drugs work.

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