A Method To Madness. Understanding Psychosis

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Few medical disorders are as stigmatizing as mental illness – particularly when it comes to the symptoms of psychosis. Though we’ve come a considerable way from the era when it was seen as demonic possession, fears and misconceptions of it continue to exist, while those who suffer from it are often afraid of the current treatments.

Fortunately, the latest research has gotten us closer to understanding psychosis – the inability to distinguish reality from one’s own hallucinations and delusions. These findings were published by the Stanford Medicine-led study on April 11 in Molecular Psychiatry, using brain scan data from children, teens and young adults diagnosed with forms of psychosis – a condition that occurs when the brain’s predictive circuitry and information processing is interfered with, according to a new theory.

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

Their test subjects had a rare genetic disease – the 22q11.2 deletion syndrome, with an emphasis on those who reported psychosis as well as a control group of individuals suffering from psychosis of unclear origin.

During a psychotic episode, patients typically experience hallucinations – hearing voic

Social withdrawal and disjointed thinking or speech are also characteristic of schizophrenia, as well as a reduction in both energy and motivation.

It is difficult to study how schizophrenia starts in the brain, with symptoms surfacing by early adulthood, when patients typically take antipsychotic medication to reduce symptoms.

When researchers look at the brain scans of people with onset schizophrenia, they are unable to discern effects of the disease from the effects of the patient’s medications. They are also unable to chart how schizophrenia alters the brain as the disease advances.

To obtain an early view of what the disease looks like, the Stanford Medicine research team observed young people from ages 6 to 39 with 22q11.2 deletion syndrome, a rare genetic condition that carries a 30% risk for either psychosis or schizophrenia or both.

“The brain patterns we identified support our theoretical models of how cognitive control systems malfunction in psychosis,” explains Vinod Menon, Ph.D., a senior author of the study and the director of the Stanford Cognitive and Systems Neuroscience Laboratory.

Thoughts that are disconnected from reality are able to ensconce themselves in the cognitive control networks of the brain. “This process derails the normal functioning of cognitive control, allowing intrusive thoughts to dominate, culminating in symptoms we recognize as psychosis,” says Menon.

Sorting it All Out

Typically, the brain’s cognitive filtration system—what neurologists call our our salience network—works as a kind of gateway, selectively directing our attention between critical internal thoughts and outside events. This is why we’re never fully lost in thought when we’re driving, as it keeps our eyes on the road when driving in traffic.

The brain’s ventral striatum and its connective brain pathways driven by dopamine, are crucial at helping us what is either rewarding or important.

For their study, the teams pieced together as much fMRI brain-scan data as they could from young people with 22q11.2 deletion syndrome. 101 individuals were scanned at three separate universities.

The study’s data also took brain scans of several different control groups without the 22q11.2 deletion syndrome: 120 were people with signs of early idiopathic psychosis, 101 people who had autism, 123 who had attention deficit/hyperactivity disorder and 411 healthy individuals.

The genetic condition associated with psychosis, is characterized by deletion of part of the 22nd chromosome, and affects 1 in every 2,000 to 4,000 individuals. Alongside a 30% risk of schizophrenia or psychosis, people who harbor the syndrome may have autism or attention deficit hyperactivity disorder.

The researchers applied a kind of machine learning algorithm they call a spatiotemporal deep neural network in order to categorize patterns of brain functioning in any patients with the 22q11.2 deletion syndrome compared against healthy individuals.

With a unit of test subjects brain scanned at the University of California, Los Angeles, the team created an algorithmic model that could differentiate brain scans of people with the 22q11.2 deletion syndrome from those who did not have it.

This model was able to predict the syndrome at an accuracy rate of 94%. They validated this model in additional control groups – people either with or without the genetic syndrome who received brain scans at UC Davis and Pontificia Universidad Católica de Chile, demonstrating that in these new groups, their model could process the brain scans with an accuracy of 84%-90%.

The research team then investigated what brain features serve the most active role in psychosis. Prior literature of psychosis has not yielded consistent results, likely due to their small sample sizes.

Comparing the brain scans of 22q11.2 deletion syndrome patients who had and those who did not have psychosis, the research team demonstrated that the brain areas most active in psychosis are the anterior insula (a basic part of our salience network, the “filter”) as well as the ventral striatum (active in reward predictions); similar findings occurred among all their study groups.

By comparing brain features in people with 22q11.2 deletion syndrome and psychosis against those who have psychosis of unknown origins, the model discovered a great deal of overlap, suggesting that such brain features are standard in general psychosis.

A subsequent mathematical model, programmed to differentiate all subjects with both 22q11.2 deletion syndrome and psychosis apart from those with the genetic syndrome and no psychosis, recognized brain scans from people with idiopathic psychosis with a 77.5% accuracy rate, again indicating that our brain’s filtering and predicting centers are crucial to psychosis.

More importantly, this model was developed specific to recognizing psychosis: It was unable to recognize disorders like idiopathic autism or ADHD.

“It was quite exciting to trace our steps back to our initial question—’What are the dysfunctional brain systems in schizophrenia?’—and to discover similar patterns in this context,” says Menon.

“At the neural level, the characteristics differentiating individuals with psychosis in 22q11.2 deletion syndrome are mirroring the pathways we’ve pinpointed in schizophrenia. This parallel reinforces our understanding of psychosis as a condition with identifiable and consistent brain signatures.”

However, these same brain signatures were not visible in people who had the genetic syndrome but no symptoms of psychosis, leaving potential clues to where future research can go.

Treating & Prevention

While supporting the scientists’ leading theory of how psychosis happens, the new findings enable us to better understand the condition—and even offer ways to prevent it.

“One of my goals is to prevent or delay development of schizophrenia,” says Supekar. The fact that the new findings are consistent with the team’s prior research on which brain centers contribute most to schizophrenia in adults suggests there may 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 disease.”

“What we saw is that, early on, functional interactions among brain regions within the same brain systems are abnormal,” he explains. “The abnormalities do not start when you are in your 20s; they are evident even when you are 7 or 8.”

The researchers intend to build off of existing treatments like transcranial magnetic stimulation or focused ultrasound that target the brain centers of young people at risk for psychosis – those exhibiting 22q11.2 deletion syndrome or have two parents with schizophrenia, to determine if they can prevent or halt the onset of schizophrenia, or even lessen the symptoms of psychosis when they occur.

Their results also indicate that the use of functional MRI to observe brain activity at key centers allow scientists to witness how available antipsychotic medications work in real time.

Although we have yet to understand why people become unhinged from reality—particularly with how dangerous it is to our well-being—the “how” is now something quantifiable, according to Supekar. “From a mechanistic point of view, it makes sense,” he adds.

“Our discoveries underscore the importance of approaching people with psychosis with compassion,”  says Menon, emphasizing that the team intends their work to not just advance our scientific understanding but to inspire cultural shifts toward empathy and offering moral support for those who deal with psychosis.

“I recently had the privilege of engaging with individuals from our department’s early psychosis treatment group,” he reflects.

“Their message was clear and powerful: ‘We share more similarities than differences. Like anyone, we experience our own highs and lows.’ Their words were a heartfelt appeal for greater empathy and understanding toward those living with this condition. It was a call to view psychosis through a lens of empathy and solidarity.”

The researchers who contributed to this new study were from UCLA, the Clinica Alemana Universidad del Desarrollo of Chile, the Pontificia Universidad Católica de Chile, and also the University of Oxford and the UC Davis.

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