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Research Roundup—What’s the Matter With White Matter in Schizophrenia?

25 September 2012. Three studies published in the Archives of General Psychiatry in September identify schizophrenia-related changes in white matter, the bundles of axons connecting different parts of the brain. Schizophrenia Research Forum takes this opportunity to survey these and other recent studies that together underscore the idea that the connections between different brain regions are not quite right in schizophrenia.

The Archives studies explore the nature of this disconnect by addressing whether white matter anomalies might predispose someone to developing schizophrenia or reflect outcomes of the disease, whether other brain measures change in tandem with white matter, and its clinical relevance. The first study, led by Paul Thompson at the University of California, Los Angeles, reports delayed white matter growth in healthy siblings of people with childhood-onset schizophrenia, and suggests this might reflect an early vulnerability that is overcome with age in siblings who do not become ill.

In a second study, Toshiya Murai and colleagues at Kyoto University in Japan find that decreased integrity of white matter containing thalamocortical connections is associated with thinner cortex—a correlation that suggests an interaction between white matter and its cortical destination, as well as a more specific role for thalamus. The third study, from Nancy Andreasen ’s group at the University of Iowa in Iowa City, finds increased white matter volume in schizophrenia that was associated with a risk allele in ZNF804A. These increases correlated with severity of psychotic symptoms, suggesting some clinical relevance.

Trait or state?
While disconnectivity could, in theory, stem from things not involving axon structure (e.g., aberrant synaptic plasticity, or loss of the synchronizing effects of certain interneurons), postmortem and brain imaging research has turned up evidence for specific white matter anomalies in schizophrenia. The new imaging studies visualize white matter with a variety of techniques, including diffusion-tensor imaging (DTI), which provides a detailed view of its structure by tracking how water flows within the axon tracts (see SRF related news story). A higher-resolution variant called diffusion spectrum MRI (DSI) reveals axon tract trajectories even as they cross paths with other axons (see SRF related news story). With DTI, the coherence of water molecule movement in one direction is summarized by fractional anisotropy (FA): low FA reflects more diffuse water movement and compromised axon tract integrity.

DTI studies have pinpointed white matter changes in both the early and chronic stages of schizophrenia (Peters et al., 2010), and a recent study finds that these occur in the absence of antipsychotic medication (Mandl et al., 2012). One critical question is whether compromised white matter flags a brain genetically prone to developing schizophrenia (trait), or instead reflects the disease process (state). Studies of unaffected relatives of people with schizophrenia help distinguish between these because relatives share some of the genetic risks, but not the disease state: if the relative has the same brain anomaly, then it could reflect a predisposing risk factor. Recent studies find evidence for such white matter traits, with reduced white matter volumes in offspring of people with schizophrenia (Francis et al., 2012) and in twins discordant for schizophrenia (Hulshoff Pol et al., 2012), and intermediate FA values for several axon tracts in unaffected first-degree relatives (Knöchel et al., 2012).

In their study published in the September issue of the Archives, first authors Nitin Gogtay and Xue Hua took a similar approach by examining white matter growth in the non-psychotic siblings of people with childhood-onset schizophrenia (COS). Studies of these rare cases in which psychosis develops before age 13 may offer a glimpse of very early aberrations in white matter growth and maturation. Gogtay and colleagues previously reported slower white matter growth in COS patients compared to age-matched controls over five years (Gogtay et al., 2008) using tensor-based morphometry, a method that can track the same brain structure as it changes shape over time. Using this method in the new study, Gogtay and Hua report slower white matter growth in the parietal lobes of 49 unaffected siblings relative to 57 controls over five years. This slowing, however, was only apparent at the youngest ages (7-14); at later ages, the participants were no different from controls, suggesting that the tardy white matter growth can catch up. Consistent with this picture of compensatory brain growth, a study published in July reported increased FA in the arcuate fasciculus of unaffected siblings relative to their siblings with schizophrenia and controls (Boos et al., 2012)—something that might indicate overgrowth to compensate for a sluggish start.

But these sorts of data don’t rule out the idea that white matter changes may also herald disease progression. A DTI study published in April suggests that white matter features reflecting a brain at risk worsen as disease unfolds (Carletti et al., 2012). The researchers found that people clinically determined to be at ultra-high risk (UHR) for developing psychosis had white matter irregularities that were not as severe as those found in people scanned at their first episode of psychosis. Yet a follow-up scan two years later revealed that those UHR people who did go on to develop psychosis exhibited a progressive FA reduction in frontal white matter, unlike the UHR group that did not develop psychosis. Whether this reduction triggers psychosis, or is a result of it, is unclear. Other recent studies support a similar association between white matter changes and early stages of disease, finding decreased FA in the fiber bundle containing axons linking the frontal lobes to the thalamus in people scanned soon after their first episode of psychosis (Lee et al., 2012), and decreased frontal white matter volume in first-episode patients when substance abusers were excluded (Colombo et al., 2012).

Shades of gray matter
Evidence abounds for changes in the neuron-rich gray matter of the brain in schizophrenia, too (see SRF related news story), leading researchers to ponder whether the white matter and gray matter changes are linked. The intricate symbiosis between an axon and its target neuron means that a single pathology could disrupt things on both ends. Such effects might arise early on: one recent small study found widespread white matter and gray matter reductions in men with first-episode psychosis relative to controls (Ruef et al., 2012), and a network analysis of gray matter and white matter in newborns whose mothers have schizophrenia (making them genetically at risk for developing the disorder) found disruptions in both, though more pronounced for white matter (Shi et al., 2012).

Another Archives paper this month, published early online September 3, addresses this issue by looking for correlations between gray matter and white matter measures. First author Manabu Kubota and colleagues focused on the thalamus’ connections to cortex, as these pathways appear disrupted in schizophrenia and have been proposed as underlying a wide range of its symptoms (Andreasen, 1997). DTI scans in 37 people with schizophrenia and 36 controls revealed reduced FA in the specific thalamocortical pathway leading to orbitofrontal cortex in schizophrenia relative to controls. Cortical thickness, a prevalent measure of brain structure in schizophrenia (see SRF related news story), was also reduced both globally and locally, including two regions targeted by the thalamus: the frontal lobe and the orbitofrontal cortex. Consistent with a link between gray and white matter, the researchers found a correlation between FA values of the right thalamo-orbitofrontal pathway and thickness of the right frontal lobe (r = 0.493) and the right lateral orbitofrontal cortex (r = 0.531) in schizophrenia only, with decreased FA associated with thinner cortex. The authors propose a few explanations for this coupling, including one originating in white matter: faulty myelination might cause axons to deliver slow or unreliable signals, impairing synaptic communication and leading to the shrinkage of dendrites on the receiving end—something that would reduce gray matter.

But what does it all mean?
Though these studies have probed for structural differences in the size or shape of specific tracts, a recent study using high-resolution MRI suggests that there may be differences in the tissue itself—alterations in the molecular makeup that are reflected in intensity differences on MRI (Kong et al., 2012). Either structural or intensity differences may reflect changes to the axons themselves, to the insulating coat of myelin that gives them their white appearance, or to the glia that make myelin (Davis et al., 2003). Even if the axonal wiring diagram is normal in schizophrenia, faulty myelination would cause information to inefficiently sputter through the brain, rendering it effectively disconnected. A new study in PNAS finds that, compared to chimpanzees, myelination in humans is particularly protracted, lasting well past adolescence, and this time course fits with the relatively late onset of schizophrenia (Miller et al., 2012).

While pinpointing white matter aberrations in schizophrenia may reveal something about its underlying pathology, mining other data realms could give way to a fuller understanding of these changes. For example, recent studies report correlations between white matter integrity and specific clinical features, which could lend some functional meaning to the voxel-based changes. One study in June found that lower FA values in anterior portions of the corpus callosum in certain tracts in schizophrenia were associated with a more severe lack of drive (Nakamura et al., 2012), and another found a relation between lower FA values in neocortical association tracts and positive symptoms, including a stronger tendency to hallucinate (Knöchel et al., 2012).

Moving from behavior to the molecular end of the spectrum, finding genetic variants that seem to shape white matter could reveal something about the mechanics of setting up and maintaining the brain’s connections. The Archives study in the September issue from Andreasen’s group incorporates both genetic and clinical clues by exploring the relationship among the gene ZNF804A, brain structure, and symptoms of schizophrenia. In a large sample of 335 people with schizophrenia and 198 controls, first author Thomas Wassink and colleagues reevaluated a single-nucleotide polymorphism (SNP) in the gene ZNF804A, called rs1344706, which has been previously associated with schizophrenia and, more broadly, psychosis. The researchers reported that the risk allele was associated with larger white matter volumes in both the schizophrenia and control groups. In the schizophrenia group, the risk allele accounted for 3.3 percent of variance in frontal lobe white matter, and carriers of the risk allele had worse psychotic symptoms than those homozygous for the non-risk allele. Despite the valuable replication of previous studies (e.g., Lencz et al., 2010), how the gene might produce these effects remains unclear. Adding to the mystery, the effect in controls runs counter to an even larger study of 892 healthy controls published earlier this year, which did not find an association between the same risk allele and brain structure, including total white matter volumes (Cousijn et al., 2012).

Such complexity may require more focused multifactorial analysis. For example, a study published in July centered just on genes encoding proteins that help sheath axons with myelin. Surveying variants in four genes, the researchers found a relationship among some of these variants, specific axon tract structure, and features of cognition (Voineskos et al., 2012). The results suggest that delving into myelin biology could provide some leads on where the white matter anomalies come from, but given the long list of potential schizophrenia candidate genes, and the variety of symptoms (and the multiple ways of measuring them), the search for meaning behind these white matter irregularities could be extensive.—Michele Solis.

Gogtay N, Hua X, Stidd R, Boyle CP, Lee S, Weisinger B, Chavez A, Giedd JN, Clasen L, Toga AW, Rapoport JL, Thompson PM. Delayed white matter growth trajectory in young nonpsychotic siblings of patients with childhood-onset schizophrenia. Arch Gen Psychiatry. 2012 Sep 1;69(9):875-84. Abstract

Kubota M, Miyata J, Sasamoto A, Sugihara G, Yoshida H, Kawada R, Fujimoto S, Tanaka Y, Sawamoto N, Fukuyama H, Takahashi H, Murai T. Thalamocortical Disconnection in the Orbitofrontal Region Associated With Cortical Thinning in Schizophrenia. Arch Gen Psychiatry. 2012 Sep. Abstract

Wassink TH, Epping EA, Rudd D, Axelsen M, Ziebell S, Fleming FW, Monson E, Ho BC, Andreasen NC. Influence of ZNF804a on Brain Structure Volumes and Symptom Severity in Individuals With Schizophrenia. Arch Gen Psychiatry. 2012 Sep 1;69(9):885-92. Abstract

Comments on Related News

Related News: Interpret With Care: Cortical Thinning in Schizophrenia

Comment by:  Cynthia Shannon Weickert, SRF Advisor
Submitted 4 January 2012
Posted 4 January 2012

Plump Enough
Thanks for your thought-provoking review of structural MRI changes in schizophrenia. I had a couple of quick comments.

You make the statement that, "Though cortical thickness itself is below the resolution of typical MRI, image analysis algorithms can now infer thickness across the entire cortical sheet as it winds its way throughout the brain." I thought sMRI gathers information for about 2 mm cubed or so. So maybe the point to make is that cortex thickness is not below the resolution, but the putative change in thickness is below the resolution. It would be interesting to know if the putative change in cortical thickness in schizophrenia could be better viewed with 3T or 7T scanners.

Also, I wonder how to interpret decreases in volume over five years that seem to be as much as 5 percent in some areas. How long could this continue to be progressive at this rate, and what would be the final cortical volume expected in the final decade of life? For example, if the DLPFC BA46 is about 3,500 microns thick, then a 5 percent loss/five years over 20 years would leave you with about 2,850 microns, and that would be about a 20 percent decrease in thickness. While postmortem studies may be limited, as Karoly points out, certainly we know that the frontal cortex is still "plump enough" to define cyto-architecturally, and to examine at the histological level. We also consider that there is about a 10 percent loss in cortical thickness in people with schizophrenia. Certainly, the cortex does not degenerate completely as would be expected with relentless progression of loss and accumulated deterioration of cortical grey matter over time.

Thus, this is an interesting issue, but many questions remain. Is there a lot of case-to-case variability that underlies these averages such that some cases lose more cortical volume and some do not lose any at all? Could it be that, while there is cortical volume loss, there are some patients in whom this loss slows or even reverses naturally over the course of the disease? What is the physical substrate of such cortical volume loss in people with schizophrenia? Can we prevent cortical volume loss over time, and would this be beneficial to patient outcomes?

View all comments by Cynthia Shannon Weickert