Gray, White Matter Changes Seen in Adolescents With Schizophrenia

Becky McCall

April 30, 2012

April 30, 2012 (Florence, Italy) — Extensive loss of gray matter during adolescence and abnormal development of white matter could contribute to the onset of schizophrenia, according to midpoint results from the North American Prodrome Longitudinal Study 2 (NAPLS 2), presented here at the 3rd Biennial Schizophrenia International Research Society (SIRS) Conference.

Tyrone Cannon, PhD, from the University of California at Los Angeles, is principal investigator for NAPLS 2, which is the largest study ever conducted in prodromal schizophrenia. It continues from the NAPLS 1 study started in 2003, which aimed to overcome the limitations of other prodromal studies available at the time by providing data on a large sample of participants and insights on biological mechanisms.

Dr. Cannon presented interim findings from one half of the potential 720 prodromal participants in the study and 180 control participants. "The main finding is that young people at risk of developing schizophrenia who actually convert to psychotic illness have a dynamic change in the amount of gray matter in their brains at that time," Dr. Cannon told Medscape Medical News.

Earlier studies, unrelated to NAPLS, which involved small samples of clinically high-risk patients, had suggested a role for progressive loss of gray matter, or "pruning," in the preceding and early stages of psychosis. The NAPLS 2 results provide similar findings on the basis of neuroimaging data in a much larger group of patients. "NAPLS 2 was designed to test this hypothesis of loss of gray matter in a more rigorous way than in earlier studies. We replicated the initial findings, and this is very encouraging," said Dr. Cannon.

Participants aged between 12 and 32 years were assessed using magnetic resonance imaging, diffusion tensor imaging, and functional magnetic resonance imaging at baseline and again at 1-year follow-up. The structure and pattern of gray matter and white matter were recorded for each participant.

"Our results showed that the change in the amount of gray matter was far more substantial than that seen in healthy subjects and even in high- risk people who do not go on to develop the disorder," reported Dr. Cannon.

To date, the researchers have recruited more than 600 ultra-high-risk prodromal youth of the 720 required from sites in the United States and Canada. In addition, 240 healthy comparison participants have also been recruited. Each participant is being followed longitudinally for 2 years, although the study is planned to run for a total of 5 years.

Dr. Cannon advanced 2 core theories to explain brain abnormalities that may potentially lead to schizophrenia.

Excessive Pruning, or Loss of Gray Matter, Seen

His first theory, which is supported by the NAPLS 2 imaging studies, suggests that pruning of neurons during adolescence is problematic in individuals who convert to psychosis. "Essentially, the pruning process that results in less gray matter happens in everyone, but it can go awry or become too aggressive and rapid, and this could cause some people to cross a critical threshold," explained Dr. Cannon.

According to Dr. Cannon, normal gray matter loss experienced during adolescence is associated with the transition into early adulthood, which makes us more capable of higher-order thinking. However, he added, "we know people cannot lose too much gray matter because it would be catastrophic, and the brain would no longer function in an integrated way."

Dr. Cannon believes this could be one potential mechanism causing schizophrenia and preventing the brain from supporting communication between neurons. "This could be among the causes," he remarked.

Early life risk factors also have a role to play in the overall effect of pruning during adolescence, Dr. Cannon explained. "For example, influenza infection of the mother during pregnancy, hypoxia during birth, and a number of the genes which confer risk are probably linked to brain development in utero. All of these factors, in some people, produce a brain that has less gray matter to begin with."

He pointed out that not every case of schizophrenia develops through abnormal pruning per se. "The process may be normal in many individuals, but it means that those who begin life with less gray matter may experience pruning during adolescence, which then lowers their total amount of gray matter below a critical threshold [which might trigger psychosis]."

Abnormal White Matter Development

In addition to excessive pruning, Dr. Cannon had another theory for why some individuals converted to psychosis whereas others did not. Specifically, this involved development of white matter or the myelin sheath surrounding the axon. "This is also associated with improved cognitive performance because the faster neurons communicate with each other the better," he said.

"In the prodromal youth, we observed an absence of the normal developmental increase in white matter as an indictor of myelination," he remarked. "We do not yet know if this is an independent process or the result of too much gray matter loss. Alternatively, the failure of white matter development might drive gray matter loss. We don't know the answer. They might even be caused by separate factors."

However, Dr. Cannon added that white matter changes were probably not secondary to gray matter changes because genomics research shows that certain genes that confer susceptibility to schizophrenia are related to oligodendrocytes and development of myelination.

"This suggests it may have a role which is not secondary to changes in gray matter, although this does not prove causality," he added.

"We believe these results provide us with some indication that the conversion to psychosis involves a developmental abnormality, and the nature of this is likely to relate to brain plasticity," remarked Dr. Cannon. He suggested that interventions aimed at promoting brain plasticity were likely to be beneficial; such interventions include the use of omega 3 fatty acids, cognitive remediation, and pharmaceutical agents currently in development.

"These lines of evidence all converge on the notion that we might be able to improve cognition in patients with the disorder and even prevent some of the disability in those at risk," he concluded.

The discussant for the session, Stephen Ruhrmann, MD, from the Department of Psychiatry and Psychotherapy, University of Cologne, Germany, said that Dr. Cannon's results replicated earlier findings on white matter changes. He added that the NAPLS 2 data enabled a further evaluation of the interplay between white matter changes, event-related potentials [brain activity related to thoughts], and functioning.

"The progressive gray matter changes demonstrated by Dr. Cannon impressively corroborate earlier findings of such dynamic alterations in converters to psychosis," he remarked.

"In my view, this seems to underline that a 'wait and observe' strategy is inappropriate if we want to avoid progression of the disease process, not only in terms of conversion but also in terms of cognitive and functional deterioration."

He added that because not all patients fulfilling clinically high-risk criteria would actually show progressive loss of gray matter, it would be important to prospectively identify these people. "They will have greatest benefit from neuroprotective interventions, perhaps fish oil. It will also be important to understand the significance of gray matter aberrations in people who do not convert to psychosis. A further breakdown of this group by other outcomes like persistent psychopathology or functional deficits may lead to further insights."

Abnormal Auditory Processing

Also presenting NAPLS 2 results at the SIRS conference was Daniel Mathalon, PhD, MD, from the University of California, San Francisco. Dr. Mathalon's interest is related to abnormalities in automatic auditory processing by the brain. Auditory regions of the brain are particularly vulnerable in schizophrenia, he noted.

He aims to identify schizophrenia biomarkers that are present in prodromal patients that can be used to improve prediction of which patients are at risk for psychosis.

Dr. Mathalon investigated the responses of high-risk patients in terms of electrophysiological responses by the brain to different types of stimuli. "We used EEG [electroencephalography]–based measures of simple information processing functions considered sensitive to schizophrenia."

P300 waves are generated when the participant is presented with infrequent events such as rare auditory or visual stimuli randomly imbedded within a series of frequently repeating stimuli. "A small P300 wave is among the most widely replicated biological abnormalities in schizophrenia, but we have not been clear on when this abnormality develops relative to the illness onset," explained Dr. Mathalon to Medscape Medical News.

He has found that the P300 wave is reduced in clinical high-risk patients relative to healthy control individuals. "In high-risk patients who went on to convert to psychosis, compared to those who did not convert by 2 years of follow-up, auditory P300 waves were reduced at baseline. Thus, small auditory P300 waves are found in the clinical high-risk patients who are most likely to go on to convert to schizophrenia. The same effect was not evident for P300 waves elicited by visual stimuli."

Also, the size of auditory and visual P300 waves declined with age faster in high-risk patients than in healthy participants. "This is consistent with an aberrant neurodevelopmental trajectory," Dr. Mathalon said.

Dr. Mathalon also found that younger age at first cannabis use was associated with smaller P300 waves in clinical high-risk patients but not in healthy comparison individuals.

NAPLS-2 is funded by the National Institutes of Mental Health. Dr. Cannon has disclosed no relevant financial relationships. Dr. Mathalon is a consultant to Pfizer and received research funding from Astra Zeneca. Dr. Ruhrmann has received support from BMS, Hoffmann-LaRoche, Servier, Pfizer, AstraZeneca, Johnson & Johnson, and the University Hospital of Cologne.

3rd Biennial Schizophrenia International Research Society (SIRS) Conference. Presented April 16, 2012.


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