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Brain Anomalies in Schizophrenia Arise Early, Degrade Connectivity

18 June 2013. Brain scans turn up plenty of anomalies in schizophrenia, but studies tend to look either at structure or function. Two new studies try for an integrated view by looking at both in the same people. One study, led by Su Lui and Qiyong Gong of West China Hospital of Sichuan University, Chengdu, China, and published online June 4 in the American Journal of Psychiatry, reports that early on in schizophrenia, certain brain regions are, on average, already smaller or larger than normal. However, these did not overlap with regions showing abnormal activity. As the largest brain imaging study yet of drug-naïve, first-episode people with schizophrenia, the findings argue that these differences accompany early stages of the illness.

The second study, led by Martijn Pieter van den Heuvel at the University Medical Center Utrecht in the Netherlands and published online June 5 in JAMA Psychiatry, used diffusion tensor imaging (DTI) and functional imaging to visualize structural and functional connectivity in established schizophrenia. The researchers report degraded “rich club” organization in schizophrenia, meaning that brain hub regions making many connections with other regions were less likely to connect to other highly connected hub regions than those in controls. This disrupted connectivity was specific to these elite hub regions, rather than a widespread feature across the brain, and correlations between structural and functional measures of connectivity were stronger in schizophrenia than in controls.

Both studies grapple with what structural differences might mean for the patterns of neural activity coursing through the brain. Each combines its structural measures with resting-state functional magnetic resonance imaging (fMRI), a technique that infers connectivity among different regions of the brain by monitoring simultaneously active regions while a subject rests quietly (see SRF related news story). While resting-state fMRI has come up with differences in the default-mode network in schizophrenia (see SRF related news story), how this corresponds to reported structural anomalies in the brain is unclear.

There early
First authors Wentig Ren and Wei Deng scanned 100 people experiencing their first episode of illness but who remained treatment naïve during the brain imaging, along with 100 controls matched for age, sex, and education. The researchers detected differences in thalamic and cortical regions in schizophrenia compared to controls; for example, they found smaller volumes in the left paracentral and left inferior parietal lobules, and larger volumes in the thalamus, anterior cingulate cortex, insula, and orbital frontal gyrus in schizophrenia.

When the researchers monitored resting-state patterns of activity in the same people, they found decreased synchrony (a proxy for strength of connectivity) in a completely different set of regions: in frontal-parietal areas and in the default-mode network—a collection of regions activated while the brain rests. This disconnect is consistent with results from the group’s previous smaller study (Lui et al., 2009) and suggests that anatomical changes reflect early pathological processes underlying the disorder, whereas functional changes indicate the state of active psychosis.

These structural and functional differences did not correlate with duration of illness or with positive symptom severity, suggesting that the brain anomalies are stable and early features of illness, though there is recent evidence that such brain abnormalities may worsen with prolonged illness (see SRF related news story). Among the study participants with schizophrenia, a substantial 36 percent had severe negative symptoms, and these showed the largest differences in brain structure, particularly in the left dorsal lateral prefrontal cortex. Their resting-state activity, however, remained similar to that of people with schizophrenia with less severe negative symptoms.

Welcome to the rich club
In the second study, first author Martijn van den Heuvel and colleagues mapped the network of connections within the brain by looking at white matter structure and resting-state activity in a group of 48 people with schizophrenia and 45 healthy controls, and in a second replication group of 41 people with schizophrenia and 51 healthy controls. Both samples of patients were relatively young (approximately 30 years of age) and almost all were currently on antipsychotic medication. The researchers then derived a global picture of the network of connections based on either the structural DTI data or the functional fMRI resting-state data (see SRF related news story). Regions with many connections to and from them are defined as hub regions, much like a hub airport on an airline flight map. These hub regions typically make more connections with other hub regions than with sparsely connected regions, and this aspect of network organization is referred to as the “rich club.”

“To put it another way, the brain’s rich club has a high capacity for integrative information processing, but also a high physical cost in terms of connection distance between club hubs,” wrote Edward Bullmore and Petra Vértes of the University of Cambridge, U.K., in an accompanying editorial in JAMA Psychiatry.

Based on the structural data, the regions belonging to the rich club in schizophrenia and in controls were the same: the precuneus, superior frontal cortex, superior parietal cortex, and insula. In both schizophrenia samples, however, the researchers found reduced density in rich club connections compared to controls. This seemed specific to rich club organization because “feeder” connections between rich club and non-rich club regions, and “local” connections between different non-rich club regions, were not significantly different between the schizophrenia groups and controls. Global efficiency, which reflects how well any region in the network can communicate with another region, was also down in schizophrenia, which might be related to the degraded rich club organization.

The researchers found a slightly stronger correlation between structural and functional measures of connectivity in schizophrenia than in controls. They suggest this may indicate that patterns of brain activity in schizophrenia are dictated more by the static, anatomical connections between regions.

Together, the studies start to outline an integrated view of brain structure and function in schizophrenia. Despite the complexity of this approach, it appears to be the wave of the future for imaging (see AbstractGollub et al., 2013) and may eventually help reveal the core brain disturbances in the disorder.—Michele Solis.

Ren W, Lui S, Deng W, Li F, Li M, Huang X, Wang Y, Li T, Sweeney JA, Gong Q. Anatomical and Functional Brain Abnormalities in Drug-Naive First-Episode Schizophrenia. Am J Psychiatry. 2013 Jun 4. Abstract

van den Heuvel MP, Sporns O, Collin G, Scheewe T, Mandl RC, Cahn W, Goñi J, Hulshoff Pol HE, Kahn RS. Abnormal Rich Club Organization and Functional Brain Dynamics in Schizophrenia. JAMA Psychiatry. 2013 Jun 5:1-10. Abstract

Bullmore E, Vértes P. From Lichtheim to Rich Club: Brain Networks and Psychiatry. JAMA Psychiatry. 2013 Jun 5:1-3. Abstract

Comments on News and Primary Papers
Primary Papers: Anatomical and Functional Brain Abnormalities in Drug-Naive First-Episode Schizophrenia.

Comment by:  Lei Wang
Submitted 17 July 2013 Posted 17 July 2013

There are two important contributions that this study...  Read more

View all comments by Lei Wang
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