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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...  Read more

View all comments by Mark Lenzenweger

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...  Read more

View all comments by Erin A. Hazlett
View all comments by Larry Siever
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