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Brain Imaging Reveals Patterns That Foreshadow Schizophrenia’s Onset

Yale Medicine Magazine, 2020 - Spring


Schizophrenia has long been a mysterious disease, but with the help of brain scanners scientists are now giving a physical shape to the delusions and hallucinations of the disorder.

Schizophrenia tends to strike people on the cusp of adulthood. Just as adolescents wrap up their education, transition to a career, and look for life partners, about one in 100 will develop the hallucinations and delusions characteristic of the condition. Many also show illogical behaviors and disorganized speech. Once in full swing, schizophrenia can derail a young adult’s life before it’s properly begun.

Signs of Schizophrenia Onset

There are often warning signs, however. In the weeks, months, or even years prior to the onset of psychosis, the adolescent may withdraw from friends, neglect personal hygiene, encounter unprecedented and inexplicable academic difficulties, or hear murmuring voices when no one else is present.

Thanks to the evolving capabilities of brain imaging approaches like fMRI, scientists are discovering telltale patterns in the cerebral networks that foreshadow the onset of schizophrenia. In the vanguard of this work is Tyrone Cannon, PhD, the Clark L. Hull Professor of Psychology and professor of psychiatry. With the help of imaging studies, Cannon’s team has shown that schizophrenia is preceded not only by a loss of gray matter, particularly in the frontal lobes of the brain, but also by altered connectivity in many brain networks, including the cerebello-thalamo-cortical circuitry.

Put differently: schizophrenia seems to be triggered by disruptions in brain connections; these disturbances start in circuits that help the brain interpret where and when an experience happens and who is involved, as well as in circuits that govern the timing and coordination of neural integration and error monitoring. Many experts now see schizophrenia “as a disease of connectivity,” said Cannon.

Genetic and Environmental Factors of Schizophrenia

But why does the wiring of the brain go awry? Schizophrenia runs in families, so there is a genetic component to the condition. Yet even in identical twins, half the time only one twin develops the disease. Environmental factors play a role, starting in the mother’s womb.

In a study published in Lancet Psychiatry, Cannon has found that the children of mothers who suffered from inflammation during their pregnancy were more likely to develop a psychotic disorder later. That finding makes sense: Inflammation is associated with increases in the level of proteins called cytokines that also interact with microglial cells involved in the elimination of synapses, the connections between brain cells. Other studies have shown that maternal undernourishment or stress during pregnancy can also interfere with the wiring of the baby’s brain.

But even though a predisposition to schizophrenia is in place at birth, schizophrenia usually develops in adolescence. At that point, the maturing brain undergoes a pruning of synapses. This process is normal; every teen loses gray matter in the process. However, some seem to experience a particularly aggressive synaptic pruning, possibly due to factors like life stressors but also by certain genetic risk variants that increase microglial cell activity. For people at risk of schizophrenia, these variants might push them over a tipping point, triggering psychosis.

Treatment Options for Schizophrenia

The effects can be devastating: Many people suffering from schizophrenia have trouble keeping jobs, become homeless, or end up in prison. About one in three will attempt suicide, and approximately every 10th person with the disorder will eventually kill themselves. Antipsychotic medications help, but only to a certain extent. “They dampen the symptoms but don’t cure the illness and also have severe side effects,” said Cannon. “Most people still have substantial problems with independent living and social functioning.”

By making schizophrenia visible, experts like Cannon hope to pave the way for treatments that are better targeted to the underlying brain mechanisms. “If we could reduce the degree of gray matter thinning in the prefrontal cortex of a young person, we might be able to make the disorder less debilitating even if we can’t fully prevent its onset.”

Already, there are signs that early interventions like cognitive behavioral therapy can blunt the impact of the disease—before it derails a young person’s life.

Originally published spring 2020; updated May 10, 2022

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