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Widespread Brain Volume Reductions in “Schizophrenia Lite”

15 February 2013. Men with schizotypal personality disorder (SPD) show reductions in brain volume in several, disparate regions, reports a study published online February 6 in JAMA Psychiatry. Led by Robert McCarley of Harvard Medical School, the brain imaging study found widespread cortical reductions in men with SPD compared to healthy controls, and these correlated with negative symptom severity. The findings highlight brain regions that might be core areas of dysfunction in schizophrenia itself.

“With SPD you have a chance to look at what may be an attenuated form of schizophrenia in a brain that hasn't been contaminated with previous medication,” McCarley told SRF. None of the participants in the study had taken antipsychotic medication.

As defined by the current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), SPD shares features of schizophrenia, like social awkwardness or perceptual abnormalities, but people with the disorder do not lose touch with reality. The International Statistical Classification of Diseases and Related Health Problems (ICD) has a similar diagnostic category—schizotypal disorder—but rather than lumping it with personality disorders, explicitly considers it a form of schizophrenia.

People with SPD may hear in the wind something like a voice, but they do not hear voices; they may engage in magical thinking like a preoccupation with UFOs, but they don’t actually believe they’ve been visited or abducted by UFOs; they may have few or no friends, but they are comfortable with that. These peculiarities do not worsen into schizophrenia, but they can interfere with a person’s ability to work or live independently. In a recent study in Schizophrenia Research, Larry Siever and colleagues of Mount Sinai School of Medicine in New York City found that people with SPD scored worse on cognitive and skills tests, and were less likely to be employed or live independently than were healthy controls or people with avoidant personality disorder (McClure et al., 2013).

Some researchers have seized upon SPD as a valuable inroad into the fundamental mechanisms behind schizophrenia, without having to deal with confounds such as medication or untreated psychosis. For example, antipsychotic medications themselves may spur brain volume loss (Ho et al., 2011), and this and some lifestyle factors have complicated efforts to discern brain changes that drive symptoms of schizophrenia from those that are consequences of living with the disorder (see SRF related news story). Because people with SPD do not tip into psychotic illness, studies of SPD can skirt these issues and potentially pinpoint brain regions at the root of schizophrenia. Despite these advantages, the study of SPD has been somewhat eclipsed recently by prodrome research, which is geared toward deciphering the subtle signs of oncoming psychotic illness (see SRF related news story).

Abnormalities in selected brain regions have been found before in SPD (Fervaha et al., 2012), but the new study is the first comprehensive look at the entire cortex. Using voxel-based morphometry and a method to accurately align brain scans for comparisons across participants, the researchers detected differences between SPD and controls not seen before.

“The surprising part was how widespread the volume reductions were,” McCarley said, noting that they found evidence for both top-down deficits in executive function and bottom-up abnormalities in sensory processing. “Our interpretation is that people with SPD have deficits not only in conceptualizing and focusing, but also in sensory perception,” he said.

Sixth sense/very shy
The trick in studying SPD is to actually find people with it. The SPD category originally arose from early genetic studies of schizophrenia, in which family pedigrees not only contained people with schizophrenia, but also people who were odd enough to make researchers hesitate in marking them as “unaffected.” This led to development of the SPD category, which is listed in the DSM-IV, and slated for the DSM-5. Despite this recognition, and an estimated prevalence of 3.9 percent, people with SPD do not usually see a physician for their odd behaviors. This means that they need to be found out in the community.

First author Takeshi Asami and colleagues did this with an advertisement in the Boston, Massachusetts, area that began, “Sixth sense/very shy,” and went on to describe recruitment for a study of people who think they have special powers, like extrasensory perception, and who are socially isolated. This garnered replies from 3,001 people, and these were whittled down through telephone and in-person interviews to 118 males with SPD. Of these, 65 underwent brain scanning, and 54 were ultimately used in the study. These were compared to a group of 54 healthy controls who, as a group, matched the age, years of education, intelligence quotient, and socioeconomic factors found in the SPD group.

Cortical reductions
The brain scans revealed a widespread pattern of small but significant cortical reductions in SPD compared to the healthy control group. These were located in many frontal, temporal, and parietal-occipital regions, and implicated centers involved in the default-mode network (see SRF related news story), sensory processing, facial recognition, and higher cognitive function. Globally, the researchers also picked up a slight difference in total gray matter volume, which constituted 42 percent of total intracranial volume in SPD compared to 43.5 percent in controls.

Unlike the brain volume losses that seem to worsen over time in schizophrenia (van Haren et al., 2011; see SRF related news story), the researchers did not find evidence for such progressive reductions in SPD. Plotting the volume of different brain regions by age of their subjects (which spanned 18-55 years), the researchers found smaller volumes in older men, but this downward trend with age was not any steeper than that found in controls.

Accentuate the negative
The cortical reductions correlated with the negative symptoms of people with SPD, as quantified using the Structured Interview for Schizotypy (SIS): those with greater reductions had more severe negative symptoms, as quantified by combining scores from items measuring social isolation, introversion, and restricted emotion and sensitivity. These correlations arose for 22 out of 26 regions with reductions—more than expected by chance. Though considered an exploratory analysis, the consistent correlations suggest these reductions are specific to negative symptoms. In contrast, no significant correlations were found for positive symptom scores.

Though future studies will have to work out how the reductions arise in the first place, the authors speculate that problems with inhibitory interneurons allow excitatory signaling to get out of hand, which creates toxic conditions that chip away at gray matter. This would occur to a lesser extent in SPD compared to schizophrenia, they suggest. If true, the difference between SPD and schizophrenia may be a matter of degree rather than kind, and something that will require ever more sensitive techniques to discern.—Michele Solis.

Asami T, Whitford TJ, Bouix S, Dickey CC, Niznikiewicz M, Shenton ME, Voglmaier MM, McCarley RW. Globally and Locally Reduced MRI Gray Matter Volumes in Neuroleptic-Naive Men With Schizotypal Personality Disorder: Association with Negative Symptoms. JAMA Psychiatry. 2013 Feb 6. Abstract

Comments on News and Primary Papers

Primary Papers: Globally and locally reduced MRI gray matter volumes in neuroleptic-naive men with schizotypal personality disorder: association with negative symptoms.

Comment by:  Mark Lenzenweger
Submitted 22 February 2013
Posted 22 February 2013

This is a very good and important new study. As someone who has studied schizotypic psychopathology for nearly three decades, and long argued that schizotypic pathology (including SPD) is a cleaner window on schizophrenia liability, I think this is a very exciting study. It highlights the incredible utility of studying schizotypic pathology as a window on causal mechanisms in schizophrenia. Unclouded by medication, institutionalization, and deterioration effects, these findings in schizotypal personality disorder shed important new light on schizophrenia (see Lenzenweger, 2010, for extended discussion of these ideas).


Lenzenweger, MF. (2010). Schizotypy and schizophrenia: The view from experimental psychopathology. New York: Guilford.

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Primary Papers: Globally and locally reduced MRI gray matter volumes in neuroleptic-naive men with schizotypal personality disorder: association with negative symptoms.

Comment by:  Erin A. HazlettLarry Siever
Submitted 26 February 2013
Posted 26 February 2013

Frontal-Temporal Gray Matter Volume and Negative Symptoms in Schizophrenia-Spectrum Disorders
The paper by Asami et al. (2013) in the latest issue of JAMA Psychiatry highlights the strengths of studying schizotypal personality disorder (SPD), which is genetically related to and shares common phenomenological, biological, and neurocognitive abnormalities with schizophrenia, but without the overt psychosis. This MRI study has several noteworthy strengths, including a large, never-medicated sample which alleviates medication as a confound. The voxel-based morphometry (VBM) MRI findings indicate reduced gray matter volume in the left superior temporal gyrus and widespread frontal, frontolimbic, and parietal regions in a sample of men with SPD compared with healthy control participants (54 in each group). Consistent with the concept that SPD probably represents a milder form of disease along the schizophrenia continuum, reduced superior temporal gyrus volume has consistently been reported in SPD and schizophrenia (Dickey et al., 2002; Hazlett et al., 2012; McCloskey et al., 2005). Additionally, Asami et al. report that smaller gray matter volume in several frontal and temporal regions was associated with greater negative symptoms (summed across social isolation, introversion, restricted emotion, and sensitivity) in the subgroup of 21 individuals with SPD examined.

These findings are of clear interest; however, some cautionary comments are warranted. First, a large number of correlations between gray matter volume and negative symptoms were conducted in a relatively small sample without correction for multiple tests. Nevertheless, the pattern of correlational findings replicates and extends prior SPD work showing an association between superior temporal gyrus volume and clinical symptom severity (Hazlett et al., 2008). Second, while the sample is large and neuroleptic naive, no females were included, making it unclear how well the results generalize to the population as a whole. Lastly, the frontal lobe volume reductions reported in this paper are in contrast with some prior MRI work providing evidence of preserved volume of the prefrontal cortex in individuals with SPD compared with healthy controls and schizophrenia patients, (e.g., Hazlett et al., 2008; Siever and Davis, 2004; Suzuki et al., 2005). It is unclear whether the source of between-study differences is due to sample characteristics (e.g., prior work included females while Asami et al. excluded them, characteristics of the healthy control comparison groups), methodological approaches to the MRI analysis (VBM vs. region-of-interest), and/or other factors. In conclusion, this paper underscores the need for further examination of the relevance of prefrontal and temporal lobe pathology, negative symptoms, and psychosis in schizophrenia-spectrum disorders.


Dickey CC, McCarley RW, Shenton ME. The brain in schizotypal personality disorder: a review of structural MRI and CT findings. Harv Rev Psychiatry . 2002 Jan-Feb ; 10(1):1-15. Abstract

Hazlett EA, Buchsbaum MS, Haznedar MM, Newmark R, Goldstein KE, Zelmanova Y, Glanton CF, Torosjan Y, New AS, Lo JN, Mitropoulou V, Siever LJ. Cortical gray and white matter volume in unmedicated schizotypal and schizophrenia patients. Schizophr Res . 2008 Apr ; 101(1-3):111-23. Abstract

Hazlett EA, Goldstein KE, Kolaitis JC. A review of structural MRI and diffusion tensor imaging in schizotypal personality disorder. Curr Psychiatry Rep . 2012 Feb ; 14(1):70-8. Abstract

McCloskey MS, Phan KL, Coccaro EF. Neuroimaging and personality disorders. Curr Psychiatry Rep . 2005 Mar ; 7(1):65-72. Abstract

Siever LJ, Davis KL. The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry . 2004 Mar ; 161(3):398-413. Abstract

Suzuki M, Zhou SY, Takahashi T, Hagino H, Kawasaki Y, Niu L, Matsui M, Seto H, Kurachi M. Differential contributions of prefrontal and temporolimbic pathology to mechanisms of psychosis. Brain . 2005 Sep ; 128(Pt 9):2109-22. Abstract

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Comments on Related News

Related News: Default Mode Network Acts Up in Schizophrenia

Comment by:  Vince Calhoun
Submitted 27 January 2009
Posted 27 January 2009

In this work the authors test for differences in the default mode network between healthy controls, patients with schizophrenia, and first degree relatives of the patients. They look at both the degree to which the default mode is modulated by a working memory task and also examine the strength of the functional connectivity. The controls are found to show the most default mode signal decrease during a task, with relatives and patients showing much less. The controls, relatives, and patients show increasing amounts of functional connectivity within the default mode regions. In addition, signal in some of the regions correlated with positive symptoms. The findings in the chronic patients and controls are consistent with our previous work in Garrity et al., 2007, which also showed significantly more functional connectivity in the default mode of schizophrenia patients and significant correlations in certain regions of the default mode with positive symptoms, and in both cases the regions we identified are similar to those shown in the Whitfield-Gabrieli paper. Our work in Kim et al., 2009, was a large multisite study showing significantly fewer default mode signal decreases for the auditory oddball task in chronic schizophrenia patients, again consistent with the Whitfield-Gabrieli paper, but in a different task.

The most interesting contribution of the Whitfield-Gabrieli paper is their inclusion of a first-degree relative group. They found that the first-degree relatives are “in between” the healthy controls and the chronic patients in terms of both the degree to which they modulate the default mode, as well as in their degree of functional connectivity. This has interesting implications in terms of the genetic aspects of the illness and suggests that the default mode may be a potential schizophrenia endophenotype. It will be interesting in future studies to examine both the heritability of the default mode patterns and their genetic underpinnings.

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Related News: Default Mode Network Acts Up in Schizophrenia

Comment by:  Edith Pomarol-Clotet
Submitted 28 January 2009
Posted 28 January 2009

The Default Mode Network and Schizophrenia
For a long time functional imaging research has focused on brain activations. However, since 2001 it has been appreciated that there is also a network of brain regions—which includes particularly two midline regions, the medial prefrontal cortex and the posterior cingulate cortex/precuneous—which deactivates during performance of a wide range of cognitive tasks. Why some brain regions should be active at rest but deactivate when tasks have to be performed is unclear, but there is intense speculation that this network is involved in functions such as self-reflection, self-monitoring, and the maintenance of one’s sense of self.

Could the default mode network be implicated in neuropsychiatric disease states? There is evidence that this is the case in autism, and a handful of studies have been also carried out in schizophrenia. Now, Whitfield-Gabrieli and colleagues report that 13 schizophrenic patients in the early phase of illness showed a failure to deactivate the anterior medial prefrontal node of the default mode network when they performed a working memory task. They also find that failure to deactivate is seen to a lesser but still significant extent in unaffected first-degree relatives of the schizophrenic patients, and that the degree of failure to deactivate is associated with both the severity of positive and negative symptoms in the patients.

Importantly, the findings of Whitfield-Gabrieli and colleagues are closely similar to those of another recent study by our group (Pomarol-Clotet et al., 2008), which found failure to deactivate in the medial prefrontal cortex node of the default mode network in 32 chronic schizophrenic patients. This is a striking convergence in the field of functional imaging studies of schizophrenia, which has previously been marked by diverse and often conflicting findings. Additionally, in both studies the magnitude of the difference between patients and controls was large and visually striking. These findings suggest that we may be dealing with an important abnormality which could be close to the disease process in schizophrenia.

If so, what does dysfunction in the default mode network mean? On the one hand, failure to deactivate part of a network whose activity normally decreases when attention has to be turned to performance of external tasks might be expected to interfere with normal cognitive operations. Consistent with this, cognitive impairment is nowadays accepted as being an important, or even a “core” feature of schizophrenia. Perhaps more importantly, could it be that default mode network dysfunction can help us understand the symptoms of schizophrenia? As Whitfield-Gabrieli and colleagues note, if the default mode network is involved in self-reflection, self-monitoring, and maintenance of one’s sense of self, then failure of deactivation might lead to an exaggerated focus on one’s own thoughts and feelings, excessive self-reference, and/or a breakdown in the boundary between the inner self and the external world. The default mode network may thus have the potential to account for two major realms of clinical abnormality in schizophrenia—its symptoms and the cognitive impairment that is frequently associated with them.

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Related News: Default Mode Network Acts Up in Schizophrenia

Comment by:  Samantha BroydEdmund Sonuga-Barke
Submitted 4 February 2009
Posted 4 February 2009

The surge in scientific interest in patterns of connectivity and activation of resting-state brain function and the default-mode network has recently extended to default-mode brain dysfunction in mental disorders (for a review, please see Broyd et al., 2008). Whitfield-Gabrieli et al. examine resting-state and (working-memory) task-related brain activity in 13 patients with early-phase schizophrenia, 13 unaffected first-degree relatives, and 13 healthy control participants. These authors report hyperconnectivity in the default-mode network in patients and relatives during rest, and note that this enhanced connectivity was correlated with psychopathology. Further, patients and relatives exhibited reduced task-related suppression (hyperactivation) of the medial prefrontal region of the default-mode network relative to the control group, even after controlling for task performance.

The findings from the Whitfield-Gabrieli paper are in accordance with those from a number of other research groups investigating possible default-mode network dysfunction in schizophrenia. For example, in a similar working memory task Pomarol-Clotet and colleagues (2008) have also shown reduced task-related suppression of medial frontal nodes of the default-mode network in 32 patients with chronic schizophrenia. However, the findings are at odds with research reporting widespread reductions in functional connectivity in the resting brain of this clinical group (e.g., Bluhm et al., 2007; Liang et al., 2006). As noted by Whitfield-Gabrieli et al., increased connectivity and reduced task-related suppression of default-mode activity may redirect attentional focus from task-related events to introspective and self-referential thought processes. The reduced anti-correlation between the task-positive and default-mode network in patients further supports and helps biologically ground suggestions of the possibility of an overzealous focus on internal thought. Perhaps even more interestingly, the study by Whitfield-Gabrieli and colleagues suggests that aberrant patterns of activation and connectivity in the default-mode network, and in particular the medial frontal region of this network, may be associated with genetic risk for schizophrenia. Although there are some inconsistencies in the literature regarding the role of the default-mode network in schizophrenia, the work of Whitfield-Gabrieli and others suggests that this network may well contribute to the pathophysiology of this disorder and is relevant to contemporary models of schizophrenia. Indeed, the recent flurry in empirical research investigating the clinical relevance of this network to mental disorder has highlighted a number of possible putative mechanisms that might link the default-mode network to disorder. Firstly, effective transitioning from the resting-state to task-related activity appears to be particularly vulnerable to dysfunction in mental disorders and may be characterized by deficits in attentional control. Sonuga-Barke and Castellanos (2007) have suggested that interference arising from a reduction in the task-related deactivation of the default-mode network may underlie the disruption of attentional control. The default-mode interference hypothesis proposes that spontaneous low-frequency activity in the default-mode network, normally attenuated during goal-directed tasks, can intrude on task-specific activity and create cyclical lapses in attention resulting in increased variability and a decline in task performance (Sonuga-Barke and Castellanos, 2007). Sonuga-Barke and Castellanos (2007) suggest that the efficacious transition from rest to task and the maintenance of task-specific activity may be moderated by trait factors such as disorder. Secondly, the degree of functional connectivity in the default-mode network may highlight problems of reduced connectivity, or excess functional connectivity (e.g., schizophrenia), which suggests a zealous focus on self-referential processing and introspective thought. Thirdly, the strength of the anti-correlation between the default-mode and task-positive networks may also indicate a clinical susceptibility to introspective or extrospective orienting. Finally, future research should continue to examine the etiology of the default-mode network in schizophrenia.


Bluhm, R.L., Miller, J., Lanius, R.A., Osuch, E.A., Boksman, K., Neufeld, R.W.J., Théberge, J., Schaefer, B., & Williamson, P. (2007). Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: Anomalies in the default network. Schizophrenia Bulletin, 33, 1004-1012. Abstract

Broyd, S.J., Demanuele, D., Debener, S., Helps, S.K., James, C.J., & Sonuga-Barke, E.J.S. (in press). Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev. 2008 Sep 9. Abstract

Liang, M., Zhou, Y., Jiang, T., Liu, Z., Tian, L., Liu, H., and Hao, Y. (2006). Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging. NeuroReport, 17, 209-213. Abstract

Pomarol-Clotet, E., Salvador, R., Sarro, S., Gomar, J., Vila, F., Martinez, A., Guerrero, A.,Ortiz-Gil, J., Sans-Sansa, B., Capdevila, A., Cebemanos, J.M., McKenna, P.J., 2008. Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default-mode network? Psychological Medicine, 38, 1185–1193. Abstract

Sonuga-Barke, E.J.S., Castellanos, F.X., 2007. Spontaneous attentional fluctuations in impaired states and pathological conditions: a neurobiological hypothesis. Neuroscience Biobehavioural Reviews, 31, 977–986. Abstract

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Related News: Default Mode Network Acts Up in Schizophrenia

Comment by:  Yuan ZhouTianzi JiangZhening Liu
Submitted 18 February 2009
Posted 22 February 2009
  I recommend the Primary Papers

The consistent findings on default-mode network in human brain have attracted the researcher’s attention to the task-independent activity. The component regions of the default-mode network, especially medial prefrontal cortex and posterior cingulate cortex/precuneus, are related to self-reflective activities and attention. Both of these functions are observed to be impaired in schizophrenia. And thus the default-mode network has also attracted more and more attention in the schizophrenia research community. The study of Whitfield-Gabrieli et al. shows a further step along this research streamline.

The authors found hyperactivity (reduced task suppression) and hyperconnectivity of the default network in schizophrenia, and found that hyperactivity and hyperconnectivity of the default network are associated with poor work memory performance and greater psychopathology in schizophrenia. And they found less anticorrelation between the medial prefrontal cortex and the right dorsolateral prefrontal cortex, a region showing increased task-related activity in schizophrenia, whether during rest or task. Furthermore, the hyperactivity in medial prefrontal cortex is negatively related to the hyperconnectivity of the default network in schizophrenia.

There are two main contributions in this work. First, they found significant correlation between the abnormalities in the default mode network and impaired cognitive performance and psychopathology in schizophrenia. Thus they propose a new explanation for the impaired working memory and attention in schizophrenia, and propose a possibility that schizophrenic symptoms, such as delusions and hallucinations, may be due to the blurred boundary between internal thoughts and external perceptions. Secondly, they recruited the first-degree relatives of these patients in this study, and found that these healthy relatives showed abnormalities in the default network similar to that of patients but to a lesser extent. This is the first study investigating the default mode network of relatives of individuals with schizophrenia. This finding indicates that the dysfunction in the default mode network is associated with genetic risk for schizophrenia.

The findings in schizophrenia are consistent with our previous work (Zhou et al., 2007), in which we also found hyperconnectivity of the default mode network during rest. Considering the differences in ethnicity of participants (Chinese in our study) and methodology, the consistency in the hyperconnectivity of the default mode network in schizophrenia is exciting, which supports the possibility that abnormality in the default-mode network may be a potential imaging biomarker to assist diagnosis of schizophrenia. However, this needs to be validated in future studies with a large sample size, due to other contradictory findings, for example, the reduced resting-state functional connectivities associated with the posterior cingulate cortex in chronic, medicated schizophrenic patients (Bluhm et al., 2007). In addition, further studies should focus on default-mode function in different clinical subtypes, as schizophrenia is a complicated disorder. Finally, it should be noticed that the hyperconnectivity of the default-mode network is not exclusively contradictory with hyperconnectivity in other regions, as we previously found (Liang et al., 2006). It is possible that hyperconnectivity and hyperconnectivity coexist in the brains of individuals with schizophrenia and together lead to the complicated symptoms and cognitive deficits.


Bluhm, R. L., Miller, J., Lanius, R. A., Osuch, E. A., Boksman, K., Neufeld, R. W., et al., 2007. Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophr Bull 33, 1004-1012. Abstract

Liang, M., Zhou, Y., Jiang, T., Liu, Z., Tian, L., Liu, H., et al., 2006. Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging. Neuroreport 17, 209-213. Abstract

Whitfield-Gabrieli, S., Thermenos, H. W., Milanovic, S., Tsuang, M. T., Faraone, S. V., McCarley, R. W., et al., 2009. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U S A 106, 1279-1284. Abstract

Zhou, Y., Liang, M., Tian, L., Wang, K., Hao, Y., Liu, H., et al., 2007. Functional disintegration in paranoid schizophrenia using resting-state fMRI. Schizophr Res 97, 194-205. Abstract

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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?

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