Cortical Thinning in Adolescence 'Definitively' Tied to Subsequent Psychosis

Megan Brooks

June 08, 2021

Subtle differences in brain morphometric features present in adolescence were associated with the subsequent development of psychosis in what is believed to be the largest neuroimaging investigation to date involving people at clinical high risk (CHR).

Investigators found widespread lower cortical thickness (CT) in individuals at CHR, consistent with previously reported CT differences in individuals with an established psychotic disorder.

Dr Maria Jalbrzikowski

"This is the first study to definitively show that there are subtle, widespread structural brain differences in high-risk youth before they develop psychosis," study investigator Maria Jalbrzikowski, PhD, assistant professor of psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, told Medscape Medical News.

The findings also suggest there are developmental periods during which certain brain abnormalities may be more apparent, "highlighting the need to consider developmental period when developing objective, biological risk factors for early intervention in psychosis," Jalbrzikowski said.

The study was published online May 5 in JAMA Psychiatry.

"Sobering" Results

The findings are based on pooled structural MRI scans from 3169 individuals recruited at 31 international sites participating in the Enhancing Neuro Imaging Genetics Through Meta-Analysis (ENIGMA) Clinical High Risk for Psychosis Working Group.

Forty-five percent of the participants were female; the mean age was 21 years (range, 9.5 to 39.9 years).

The cohort included 1792 individuals at CHR for psychosis and 1377 healthy control persons. Using longitudinal clinical information, the researchers identified 253 individuals at CHR who went on to develop a psychotic disorder (CHR-PS+) and 1234 at CHR who did not develop a psychotic disorder (CHR-PS-). For the remaining 305 individuals at CHR, follow-up data were unavailable.

Compared with healthy control persons, individuals at CHR had widespread lower CT measures but not lower surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with conversion to psychosis.

The pattern of differences in cortical thickness in those in the CHR-PS+ group mirrored patterns seen in people with schizophrenia and in people with 22q11.2 microdeletion syndrome who developed a psychotic disorder.

The researchers note that although all individuals experience cortical thinning as they move into adulthood, in their study, cortical thinning was already present in participants aged 12 to 16 years who developed psychosis.

"We don't yet know exactly what this means, but adolescence is a critical time in a child's life ― it's a time of opportunity to take risks and explore, but also a period of vulnerability," Jalbrzikowski said in a news release.

"We could be seeing the result of something that happened even earlier in brain development but only begins to influence behavior during this developmental stage," she noted.

This analysis represents the largest-ever pooling of brain scans in children and young adults who were determined by psychiatric assessment to be at high risk of developing psychosis.

"These results were, in a sense, sobering. On the one hand, our dataset includes 600% more high-risk youth who developed psychosis than any existing study, allowing us to see statistically significant results in brain structure.

"But the variance between whether or not a high-risk youth develops psychosis is so small that it would be impossible to see a difference at the individual level," Jalbrzikowski said.

More work is needed in order for the findings to be translated into clinical care, she added.

Definitive Findings

Commenting on the findings for Medscape Medical News, Russell Margolis, MD, clinical director, Johns Hopkins Schizophrenia Center, said that "it's not so much that the findings are novel but rather that they're fairly definitive in that this is by far the largest study of its kind looking at this particular question, and that gives it power. The problem with imaging studies has often been inconsistent results from study to study because of small sample size.

"In order to see these differences in a robust way, you need a large sample size, meaning that for any one individual, this kind of structural imaging is not going to add much to the prediction of whether someone will eventually develop a schizophrenia-like illness," said Margolis, professor of psychiatry and behavioral sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

From a clinical standpoint, Margolis said the findings probably won't change practice, but they have implications for understanding the neurobiology of psychotic disorders.

"The predominant hypothesis in the field is that early developmental abnormalities are the root cause of schizophrenia and related disorders, and this study is consistent with that, particularly the age-related differences, which are suggestive of neurodevelopmental abnormalities preceding the development of overt symptoms, which many other findings have also suggested," Margolis said.

"Abnormalities in cortical thickness could be from a number of different neurobiological processes, and research into those processes are worth investigating," he added.

The researchers received support from numerous funders, all of which are listed in the original article, along with author disclosures for ENIGMA working group members. Margolis has disclosed no relevant financial relationships.

JAMA Psychiatry. Published online May 5, 2021. Abstract

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