Science Advances Begin to Reveal Schizophrenia's Early Brain Changes

Childhood-onset schizophrenia is extremely rare, but recent studies demonstrate an association with brain development and circuitry patterns that are helping to define the illness, said speakers at the American Academy of Child and Adolescent Psychiatry's annual meeting in Honolulu in October.

“Childhood-onset schizophrenia has clear origins in disruptions during brain development,” said Robert Asarnow, Ph.D., a professor of psychiatry and behavioral science and professor of psychology at the David Geffen School of Medicine at UCLA. Cognitive and imaging studies at UCLA, the National Institute of Mental Health (NIMH), and elsewhere provide insight into what circuits of the brain are disrupted in schizophrenia and thus into possible therapies.

Patterns can be seen even before symptoms appear, said Asarnow.

“A history of speech, language, and motor development problems before 30 months of age was found in 60 percent to 72 percent in studies at UCLA and NIMH,” he said. Prodromal symptoms at ages 7 to 10 also include inattention, reduced concentration, social isolation, and “attenuated” positive and negative symptoms.

However, in adolescents with childhood-onset schizophrenia, expressive language skills are impaired least, so in prodromal individuals, language problems represent a delay but not a failure in acquiring skills that are on the cusp of development.

Adding a secondary mental task impairs processing performance in these patients. Asarnow likens the problem to learning to ride a bicycle. At first, the riders' entire attention is concentrated on the mechanics of riding the bike. Once they learn that, they can ride and also hold a conversation or appreciate the scenery.

“Less cortical activation is needed for the primary task, which frees up the brain's processing resources,” he said. Cognitively, childhood-onset patients never get out of that first phase. “It's not clear if one cognitive process is impaired or if the abilities of the brain to remold itself are degraded.”

Research shows that neurocognitive impairments in childhood-onset schizophrenia reflect liability to schizophrenia and are not just an epiphenomenon of psychiatric symptoms or of medications, said Asarnow. More remains to be learned, however.

“There is a lot of leverage to be gained from challenging the underlying neural circuits of the brain to remold [the brain] by studying children and adults with schizophrenia as they're acquiring knowledge and skills.”

Childhood-onset schizophrenia appears in only 1 in 30,000 to 50,000 children under age 13, said Nitin Gogtay, M.D., of the Child Psychiatry Branch at NIMH. Children in NIMH studies are diagnosed using unmodified DSM-III/IV criteria, after a complete medication washout. About 30 percent leave without a schizophrenia diagnosis but are followed up to ensure diagnostic consistency.

There are advantages to studying children with an average age of 10.4 years, said Gogtay. Probands and their siblings are younger and still developing, so developmental changes can be tracked. There are fewer environmental influences on their brains (like smoking or alcohol), and hence genetic factors are more salient.

In a number of imaging studies, Gogtay and others have observed a variety of changes in brain structure, both over time and in comparison with healthy control subjects. Patients' brains show lower cerebral volume, reduced gray matter, and slower annual white matter growth.

“Gray matter loss in these young children gets localized in the prefrontal and temporal cortices,” he said.

Among patients brought into his clinic who did not develop schizophrenia but who were diagnosed with psychosis NOS, about 40 percent later developed bipolar disorder. Gogtay thus had brain scans on these children both before and after their first manic episode and found no neurobiological overlap between patients with bipolar disorder and those with schizophrenia.

Genetic factors likely play a role in childhood-onset schizophrenia. Healthy siblings of the patients had some gray matter deficits at age 8 but had normalized by age 17. Candidate gene studies of the COMT gene found that its Val-Val allele produced a steeper gray matter loss among patients and their siblings.

Ultimately, gray matter loss slows over time, merging with the adult-onset pattern, implying a biological continuity between childhood-onset and adult-onset versions of the disorder, said Gogtay.