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Interpret With Care: Cortical Thinning in Schizophrenia

23 November 2011. Of all the parts of the brain, researchers are seizing upon one of the skinniest to understand neural dysfunction in schizophrenia. Only a few millimeters thick, the cortical layer contains the neurons and connections that comprise much of the brain’s workforce, and appears abnormally thin in multiple magnetic resonance imaging (MRI) studies in schizophrenia. And it grows thinner with time, according to the first longitudinal study of adults with schizophrenia, led by René Kahn of University Center Utrecht in The Netherlands and published in the September issue of the Archives of General Psychiatry.

As a heritable quality (Panizzon et al., 2009) linked to cognition (Ehrlich et al., 2011), cortical thickness offers the tantalizing prospect of insight into the brain circuitry affected in schizophrenia. 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 wends its way throughout the brain. Frontal and temporal regions consistently come up thinner in schizophrenia (e.g., Kuperberg et al., 2003)—so consistently that cortical thickness has recently been used as one of several measures in an attempt to automatically distinguish brain scans of individuals with schizophrenia from those of controls (Takayanagi et al., 2011).

But just what to make of the submillimeter deficits detected by these studies is unclear. On a micro-level, researchers are uncertain about the type of brain change giving rise to the thinner MRI measurements. On a macro-level, they are still debating how, if at all, thinning relates to schizophrenia. The new study by Kahn's group raises the specter of progressive tissue loss, with a rate of thinning five times that found in controls. But whether the thinning marks a worrisome driver of pathology, a harmless byproduct of mental illness, or something else entirely will be a challenge to disentangle.

“I totally accept that the MRI findings are real,” said Daniel Weinberger of the Lieber Institute for Brain Development in Baltimore, Maryland. “The only question here is whether the findings inform us about something fundamental to the brain in schizophrenia.”

At the very least, cortical thinning may be part of the wholesale reductions in cortical volume observed time and again in schizophrenia (see SRF related news story). Deconstructing cortex volume into its component parts of thickness and area may provide a more mechanistic view of the brain changes associated with schizophrenia.

“We think that cortical thickness and cortical area come online at different stages, that they might have different trajectories in time, and that they are determined genetically but in different ways,” Ingrid Agartz of the University of Oslo, Norway, told SRF. Agartz was not involved in the new study, but she and colleagues recently found a genetic association with cortical thickness (see SRF related news story), which might influence disease progression in schizophrenia.

“By separating out this thing called cortical volume into area and thickness, we can increase the accuracy of what we are really trying to find, which is an etiological and pathophysiological understanding of the disease,” Agartz said.

The longitudinal view
The challenge, however, lies in sorting out the specifics of the cortical thinning-schizophrenia link. Even just narrowing in on when cortical thinning arises eludes researchers, with cross-sectional studies comparing different groups at a single time point coming up with mixed conclusions. Some find thinning early on: the anterior cingulate cortex appears thinner in people who eventually become psychotic compared to those who don’t (Fornito et al., 2008), and a recent first-episode study found that cortical thinning was not influenced by age, gender, age of onset, duration of illness, or clinical symptoms (Crespo-Facorro et al., 2011). Another recent study finds that thinning distinguishes a subtype of schizophrenia with cognitive impairment, and so could be involved in its particular etiology (Cobia et al., 2011). These sorts of findings suggest that thinning reflects an aberration in early brain development, and contributes to schizophrenia liability.

Yet other studies find thinning comes later, either with illness onset or beyond. For example, first-episode patients imaged soon after psychosis onset exhibit significant cortical thinning compared to controls (Narr et al., 2005), and a study early this year of mainly chronic patients links thinning to illness onset (Kubota et al., 2011). Other studies invoke disease progression, with more pronounced thinning found in older people with schizophrenia (Wiegand et al., 2004) that was also independent of antipsychotic medication (Nesvåg et al., 2008).

“You have the disease itself, you have lifestyle, you have medication procedures that change over time, you have the fact that there is a clinical heterogeneity within schizophrenia, and there's also genetic variation,” Agartz said. “All these different effects are difficult to disentangle, but longitudinal studies might be able to address some of these actions,” she said.

Longitudinal studies also touch on the nature of schizophrenia itself. Does the expression of the illness unfold as the brain tries to cope with a fixed neurological insult that happened early on, or is it actively driven throughout life by some brain-damaging process? By tracking brain features in the same people over time, longitudinal studies can address whether a particular brain anomaly is fixed or changing. Though these views are sometimes pitted against each other as neurodevelopment versus neurodegeneration (Weinberger and McClure, 2002 and Mathalon et al., 2003), they are not necessarily mutually exclusive. Multiple pathological processes that together include both categories may coexist, or a single brain change may arise first early in development, but then worsen later (Pantelis et al., 2005).

Cortical thinning might fit the there-early-but-progresses-later notion: on top of the abnormally thin cortex apparent early on, and the correlation between thinning and age, longitudinal studies are starting to detect progressive thinning with time. For example, a longitudinal study of adolescents with rare, childhood-onset schizophrenia reported cortical thinning that progressed throughout the brain over five years (Thompson et al., 2001). And now, in the new longitudinal study of more typical, chronically ill patients, excessive thinning is also found over five years. While these results don’t rule out additional effects of neurodevelopmental or illness-onset brain changes, they highlight the dynamic nature of the brain in disease, and provocatively suggest that finding ways to stall thinning might improve outcomes.

“There might be multiple waves of cortical thinning throughout life—we really have no clue how these processes work,” says Neeltje van Haren, first author of the recent longitudinal study in adults. “Our study shows there is excessive thinning in the cortex in chronically ill stages, not just early in the illness.”

Stretched thin
Using samples examined in a previous study of brain volume (van Haren et al., 2008), van Haren and colleagues compared MRI scans from 96 individuals with schizophrenia and 113 healthy controls. At baseline, the average cortical thickness across the entire brain was about 3 mm and did not differ between the two groups, but regionally, the schizophrenia group exhibited a thinner cortex in the frontal and temporal lobes. Five years later, the schizophrenia group lost an average of 0.05 mm of cortex thickness, while healthy controls only lost 0.01 mm. Even more profound thinning ranging from 0.05 to 0.19 mm could be detected within the frontal and temporal regions.

These hair-thin decrements in cortical thickness were associated with medication intake and functional outcome. A higher amount of typical antipsychotic use during the five years between scans was associated with larger declines in cortical thickness in several brain regions compared to atypical antipsychotics. Though the strength of the effect for atypicals versus typicals varies across studies, the finding fits with antipsychotic-induced changes in brain structure found for brain volume (Ho et al., 2011) and in animal studies (e.g., Vernon et al., 2010).

Van Haren noted that the influence of antipsychotics on brain structure is a hot topic these days (see, e.g., recent comment by Lieberman), but antipsychotics didn’t explain everything in her study. Extensive thinning in the left superior temporal cortex was linked to poor functional outcome, as assessed by a combination of functional and symptomatic measures, in a way that was independent of medication. This dissociation helps rule out the possibility that the most ill had most thinning because they took the most medication.

But distinguishing cause from consequence is tricky. Does thinning drive poor outcome, or does it reflect consequences of a poor outcome, with psychosis or other aspects of the disease literally sculpting the brain? Though current circumstantial evidence for early thinning suggests thinning comes first and drives illness, van Haren said it is far from definitive.

“We cannot give direction to the associations that we find. Based on these kinds of data, it could go either way,” van Haren said. In an ideal world, population-based, longitudinal studies involving frequent brain scans and comprehensive phenotypical data might capture whether this sort of brain change comes before or after illness.

“We really have to scan people before any problems are visible,” she said. “Otherwise I don't see how you can ever distinguish between the chicken and the egg.”

Less intact or artifact?
Others worry that cortical thinning is not related to disease at all, but is merely an epiphenomenon reflecting the different lifestyles of mentally ill people. Weinberger emphasizes that lifestyle variables such as exercise, smoking, and weight gain can push around MRI measures of cortex.

“There are so many things that change the dimensions of these measurements on an MRI scan that are about normal, everyday living characteristics that it's very hard to know what changes in a group of patients with schizophrenia followed for five years represent,” Weinberger told SRF.

Though smoking, and alcohol and drug use were ruled out in van Haren’s study, she said other variables like exercise, cannabis use (Rais et al., 2010), and IQ were being examined.

“I do agree that this is going to be one of the main issues in the next few years, and we haven't even begun to look at how the different confounders interact,” van Haren said. “But I would be surprised if cortical thinning could all be accounted for by lifestyle.”

Weinberger also questions whether MRI results reflect a true structural change in the brain, noting a lack of a postmortem correlate for tissue loss. Without such a correlate, lifestyle-induced physiological variations in the brain, such as changes in blood perfusion, fat content, and water relaxation times, may be more important. “These have nothing to do with the brain becoming less intact,” Weinberger said.

Others point out that MRI-detected thinning could reflect a decrease in the connections made between neurons. Though widespread neuron die-off characteristic of neurodegenerative disorders like Alzheimer's disease has never been detected in postmortem studies of schizophrenia, decreases in the neuropil—the thicket of dendritic trees and connecting axonal branches—have been reported (Selemon et al., 1998; Fornito et al., 2009), and could conceivably contribute to the MRI-detected thinning.

Though neuropil reductions did not always result in a thinner cortex, it may be that MRI studies are outpacing the postmortem ones. Typically conducted on small samples in discrete cortical regions, postmortem studies probably do not have the power to detect the cortical thinning found in MRI studies that look at the entire brain in many more individuals, said Karoly Mirnics of Vanderbilt University in Nashville, Tennessee, who was not involved in the new longitudinal study.

“I believe that the shrinkage is small, but real,” Mirnics told SRF. “But whether it is of clinical consequence is unclear.”

It would be optimal to examine postmortem brain samples from people who participated in MRI studies, Agartz said. “Ideally, one would be able to study someone from the cradle to the grave.”

Clinical conundrums
Sorting out the clinical relevance, if any, of these subtle changes in cortical thickness will be helped by clinical measures sensitive enough to track changes in a person’s symptoms and function over time. Is progressive cortical thinning always associated with clinical deterioration? What happens in those who remain relatively stable?

Longitudinal studies might skim over this issue, because study participants who are available for multiple scanning sessions over long periods of time tend to be clinically stable. To address this, Agartz cites the need to standardize MRI protocols as a step toward sharing data. “Sometimes you wonder if your results are methods-based or cohort-based, so this kind of exchange could be of value,” she said.

Scanning individuals who do not have schizophrenia may also help fill in the meaning of cortical thinning. Last year, Agartz and colleagues found a partially overlapping pattern of thinning between the bipolar disorder subtype that comes with mania and schizophrenia (Rimol et al., 2010). The thinning was not related to medication, and could reflect shared aspects of the two disorders in terms of genetic liability or symptoms. Clues to the genetic influence on cortical thinning also come from studies including healthy relatives, with unaffected offspring of individuals with schizophrenia showing decreased cortical thickness (Bhojraj et al., 2011), but only trends for thinning in unaffected siblings (Goldman et al., 2009). Earlier this year, a single nucleotide polymorphism on 15q12 was associated with cortical thickness, but not schizophrenia (Bakken et al., 2011). These findings suggest that cortical thickness interacts with other risk factors to influence the liability or disease course of schizophrenia.

Despite the evidence for genetic influence on cortical thickness, understanding just how malleable it is may give rise to new treatment strategies. If thinning reflects a true structural change in the brain related to disease, is it permanent or reversible? If reversible, what drives it? Does cortical thickness fluctuate as a result of experience-dependent plasticity, in which aspects of the disease, like psychosis, leave their mark on the brain? Or does thinning reflect impaired plasticity, with the brain unable to respond appropriately to environmental inputs—a notion in line with the underactive glutamate system hypothesized for schizophrenia (see SRF hypothesis)? If so, finding ways to restore plasticity, or normalize cortical thickness, might improve outcomes.

“How plastic is the brain? Can we reverse some of this thinning by affecting, for instance, synaptic function?” Agartz asked. “There need to be more studies.”—Michele Solis.

van Haren NE, Schnack HG, Cahn W, van den Heuvel MP, Lepage C, Collins L, Evans AC, Hulshoff Pol HE, Kahn RS. Changes in cortical thickness during the course of illness in schizophrenia. Arch Gen Psychiatry. 2011 Sep;68(9):871-80. Abstract

Comments on News and Primary Papers

Primary Papers: Changes in cortical thickness during the course of illness in schizophrenia.

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 16 September 2011
Posted 16 September 2011
  I recommend this paper

I am still struggling with the concept of cortical thinning in patients over time. I think this and previous studies have clearly demonstrated that there is a progressive cortical thinning in schizophrenia, which is also associated with poor clinical outcome. The higher cumulative intake of typical antipsychotics during the scan interval was associated with more pronounced cortical thinning in the current study, but this can be interpreted in multiple ways. Anyhow, I still have an unresolved issue in my mind: if cortical thinning is bad and impairs brain function, why is this progressive thinning not associated with much more pronounced clinical deterioration over the lifetime? Any comments?

View all comments by Karoly MirnicsComment 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

Comments on Related News

Related News: Schizophrenia and Neurodegeneration—Case Bolstered by MRI, Electrophysiology

Comment by:  Dan Javitt, SRF Advisor
Submitted 29 May 2007
Posted 29 May 2007

Salisbury et al., in the May 2007 issue of Archives of General Psychiatry, demonstrate associated progressive reductions in mismatch negativity (MMN) amplitude and Heschl’s gyrus reduction in schizophrenia. These findings provide strong support for involvement of auditory cortex in the pathogenesis of schizophrenia, and demonstrate that pathological changes in the illness are not confined to specific brain regions, such as prefrontal cortex, that receive the preponderance of attention.

Further, the manuscript helps resolve an important current controversy in the MMN literature. Deficits in MMN generation have been among the most consistent findings in chronic schizophrenia, with a recent meta-analysis showing large (~1 sd unit) effect size MMN reductions across studies (Umbricht et al., 2005). As noted by Salisbury et al., however, deficits have not been observed in first-episode patients (Salisbury et al., 2002; Umbricht et al., 2006). An unknown issue was whether the discrepancy between first-episode and chronic patients was due to within-subject change (the “degeneration” hypothesis), or whether those patients with small MMN at entry tended to be retained disproportionately in chronic samples because of the relationship between MMN generation and global outcome (e.g., Light and Braff, 2005) (the “distillation” hypothesis).

The present study suggests that at least some patients show reductions of both MMN amplitude and left HG volumes over time, lending at least partial support for the degeneration hypothesis. This finding is important in that it shows that the pathological process contributing to cognitive impairment in schizophrenia continues beyond first episode, and may be a target for pro-cognitive interventions. It should be noted that the degeneration continued despite treatment with atypical, as well as typical, antipsychotic medication.

As noted by Salisbury et al., the change in MR volume in schizophrenia is best conceived as atrophy of neurons, rather than degeneration. On a histological level, the volume reductions noted on MR correspond with reduced pyramidal cell size in postmortem tissue (e.g., Sweet et al., 2004). Interestingly, postmortem studies have yet to show volumetric reductions in HG despite the change in some compartments, suggesting that MR may be detecting changes in tissue parameters that are not apparent in postmortem histological examination. This study also complements a recent diffusion tensor imaging (DTI) study that showed correlations between white matter changes in auditory projection pathways and auditory processing deficits in schizophrenia (Leitman et al., 2007). The relationship between white matter and grey matter pathology requires further investigation.

There are additional lessons hidden in the Salisbury et al. study. Given the relationship between reduced MMN generation (a functional measure) and cortical volume (a structural measure), there is a strong tendency to assume that structural changes are the cause of functional changes. The findings by Salisbury et al., as well as the extrapolation to postmortem histological studies, argue strongly against such an interpretation. For example, in the Salisbury et al. study, the change in left HG volume from time 1 to time 2 was only 6 percent, whereas MMN declined by 33 percent over the same period of time. At time 2, HG volumes were only 2 percent smaller in schizophrenia patients vs. controls, whereas MMN was 35 percent smaller. These findings suggest that simple volume loss does not cause the reduction in MMN. Further, even though MMN reduction seems to stabilize following the first 1.5 years (e.g., Umbricht et al., 2006; Javitt et al., 1995), this may not be the case with volumetric deficits. Thus, in a prior sample of chronic patients, this same group reported reductions of 13 percent in HG volume (Hirayasu et al., 2000), as opposed to the 2 percent reduction observed in patients following 1.5-year follow-up. Rather than suggesting a primary role of degeneration, this suggests a “use it or lose it” relationship within auditory cortex, wherein persistent reduction of activity may lead over time to structural involution. Even in postmortem studies (e.g., Sweet et al., 2004), pyramidal cell volumes are reduced by only 10 percent, whereas MMN in chronic schizophrenia may be reduced by 40 percent or more (e.g., Salisbury et al., 2002; Umbricht et al., 2006).

As noted by Salisbury et al., acute treatment with NMDA antagonists leads to reduced MMN amplitude in both human (Umbricht et al., 2000) and animal (Javitt et al., 1996) models. NMDA receptors also play a critical role in synaptic spine development and maintenance (Matsuzaki et al., 2004). A possible explanation, therefore, is that reduced NMDA activity in auditory cortex leads to both MMN reductions and reductions in spine density. Alternatively, primary alteration in subpopulations of cortical glutamatergic cells could trigger the sequence of events leading to reduced MMN generation.

There are several other intriguing features to the dataset. For example, at baseline, there were several controls who had larger than median HG volumes, but nevertheless failed to generate MMN (i.e., <1 μV). In schizophrenia patients, this sector of the plot was entirely empty and the only subjects who failed to generate MMN were those with small HG volumes. This suggests that there may be fundamental differences in structure/function relationships. It is almost as interesting to know why some controls fail to generate MMN despite having adequate HG size, as it is to know why HG is reduced in schizophrenia.

The finding that the relationships hold only for left, not right, HG, also is worthy of further investigation, as is the finding that right HG volumes are reduced even at first episode and do not decline further. Finally, the correlation on reduced MMN amplitude at Fz with reduced HG volume reiterates once again the role of auditory, rather than frontal, cortices in mediating MMN generation deficits in schizophrenia.

View all comments by Dan Javitt

Related News: Schizophrenia and Neurodegeneration—Case Bolstered by MRI, Electrophysiology

Comment by:  Lei Wang
Submitted 5 June 2007
Posted 5 June 2007

The authors reported a cross-sectional (first hospitalization or within 1 year of first hospitalization) and longitudinal (1.5-year follow-up) study of electrophysiologic testing (mismatch negativity, or MMN, amplitude) and high-resolution structural magnetic resonance imaging of Heschl gyrus and planum temporale gray matter volumes. Schizophrenia subjects showed longitudinal volume reduction of left hemisphere Heschl gyrus (P = .003), which was highly correlated with MMN reduction (r = 0.6; P = .04). The interrelated progressive reduction of functional and structural measures suggests progressive pathologic processes early in schizophrenia. The design of the study helped minimize the effect of medication, the authors commented, therefore allowing the interpretation that brain change is due to disease progression.

From an imaging perspective, this is a straightforward longitudinal study of brain structure following previously published image processing and measuring protocols (Kasai et al., 2003). T1- and T2-weighted MR scans were acquired using the same sequence and on the same scanner for all subjects and at all time points. All baseline and follow-up MR scans were bias-field corrected and used in a fully automated segmentation algorithm for tissue classification, and then realigned to standard coordinate space and re-sampled to isotropic voxel resolution for application of standard manual segmentation protocols. Intracranial content was also estimated. Inter-rater and intra-rater reliability for segmentation of the Heschl gyrus and planum temporale was very high (volume ICC ranging from 0.95 to 0.99) (Kasai et al., 2003).

The authors showed in their earlier paper (Kasai et al., 2003) that using this approach, the time-dependent change in the volume of intracranial content did not correlate with time-dependent volume changes of brain structures. While this is reassuring, a trend-level decrease of intracranial content in time (p = 0.065), however, does raise the possibility of some systematic bias such as scanner drift resulting in global scaling, especially considering the subjects’ ages of 21-24 years. Some solutions such as scaling the follow-up scans with respect to the baseline scans could be evaluated (Freeborough and Fox, 1997).

This well-designed and well-presented study adds to a growing body of evidence that longitudinal structural neuroimaging is an effective way to detect progressive changes in specific brain structure in patients with schizophrenia. The results of this study contribute to the debate over whether the pathogenesis of schizophrenia includes a neurodegenerative as well as neurodevelopmental component.

View all comments by Lei Wang

Related News: Schizophrenia and Neurodegeneration—Case Bolstered by MRI, Electrophysiology

Comment by:  Robert McClure (Disclosure)
Submitted 10 June 2007
Posted 10 June 2007

Longitudinal increases in volume of the lateral ventricles and decreases in brain volume—progressive changes—are often observed over time early in the course of schizophrenia. There is not uniform agreement over the proper interpretation of these changes, prompting vigorous, healthy debate among investigators. A major point of contention appears to be whether these volume changes actually constitute evidence of active disease progression.

In the current study, the authors seek to bolster the case for structural progression by demonstrating evidence of interrelated progressive functional impairment. They buttress the case for structural progression by demonstrating a relationship between worsening deficit in mismatch negativity and auditory cortex volume decreases.

Identification of a direct causal relationship between the underlying pathophysiology of schizophrenia and volume losses observed early in the illness would conclusively demonstrate structural progression. Such a direct link has not yet been established, so the results of this study constitute only indirect evidence that structural progression is tied to the emergence of functional impairment. Results of longitudinal MRI studies are useful for identify factors potentially associated with these volume changes, including altered neurodevelopment, disease progression, mismatch negativity, antipsychotic medications, and yet unidentified factors. Until the underlying etiology of schizophrenia is known, what underlies longitudinal volume change in schizophrenia is unlikely to be determined.

Future research should focus on specifying the neurodevelopmental mechanisms that contribute to the cortical pathology central to schizophrenia.

View all comments by Robert McClure