October 27, 2005

The Schizophrenia Spectrum

Recent Schizophrenia Research Reviews, By Demian Rose, MD, PhD

"Brain Connectivity and the Schizophrenia Spectrum", a summary review of:

Fronto-Temporal Disconnectivity in Schizotypal Personality Disorder: A Diffusion Tensor Imaging Study

Introduction to the Topic
There is ample evidence from family and genetic studies to suggest that schizophrenia is related to a less severe diagnosis known as “Schizotypal Personality Disorder” (SPD). The criteria for SPD share many of the criteria for a diagnosis of schizophrenia, including a pervasive pattern of disruption in social relationships, unusual sensations and perceptions, odd beliefs not consistent with cultural norms (“magical thinking”) and a restricted range of emotional expressivity. Unlike schizophrenia, however, SPD is generally not chronically debilitating, does not involved frank hallucinations or significant cognitive impairments, and rarely benefits from the use of anti-psychotic medications. These observations have prompted some to speak of a “schizophrenia spectrum”, described as a range of deficits that extend from mild to severe, likely related to altered anatomy of similar brain structures.

Given that schizophrenia often evolves out of an early “prodromal” period, where symptoms and social functioning worsen gradually, it is often difficult to discriminate it from SPD in an adolescent or young adult who begins to show evidence of magical thinking or socially isolative behavior. It would therefore be useful to look for tests that may be able to better predict the likelihood that a particular individual will eventually develop a relatively benign – if still socially impairing – condition vs. one that may require frequent hospitalization or assisted living. The study below is one that attempts to use neuro-imaging (“brain scans”) to look for reliable differences in brain anatomy between people with SPD, those with schizophrenia, and those who have neither condition.

Who did the study
The authors are associated with the Department of Psychiatry at Harvard University in Boston. They have previously studied brain connectivity in people with schizophrenia, using the same imaging technique they apply in this study to people with schizotypal personality disorder.

Why they did the study
As mentioned above, schizotypal personality and schizophrenia have often been thought of as two disorders that were similar in the types of phenomena associated with them, but not the degree to which these phenomena were expressed – the latter disease is much more disabling. This concept of a “spectrum” does, however, bring up many unanswered questions. In this study, the major question they set out to answer was this: is brain connectivity in two distinct areas of the brain altered in people with schizotypal personality disorder (SPD) in the same manner as it is altered in people with schizophrenia?

It has previously been shown with neuro-imaging that reproducible differences are seen in the frontal and temporal lobes of brains of people with schizophrenia. Using the newest imaging technique – an offshoot of functional magnetic resonance imaging known as diffusion tensor imaging (DTI), which is able to measure brain connectivity as seen in the white matter fiber bundles of the brain (“nerve highways”) – previous studies have demonstrated that one of the most frequent findings is that two of the white matter fiber bundles connecting the prefrontal and temporal lobes of the brain are abnormal in schizophrenia.

In people with SPD, structural (anatomical) imaging studies have shown reduced volume in brain regions that also show decreased volume in schizophrenia. These changes are in gray matter portions of the brain, were the cell bodies of the nerves lie. What had not yet been investigated at the time of this study was whether people with SPD also had similar changes in white matter, i.e. brain connectivity, to those seen in schizophrenia. The authors focus their attention on two particular white matter fiber bundles, called the uncinate fasciculus (UF) and the cingulum bundle (CB), as both of these connect areas of the brain known to be affected in schizophrenia, and have previously been shown, using DTI, to have abnormal connectivity and structural disorganization.

How they designed the study
Before I enter into an overview of the study design itself, it is first worth a brief note about diffusion tensor imaging (DTI). A DTI brain scanner is in many ways similar to a functional magnetic resonance imaging (fMRI) scanner. fMRI scanners have been used for many years to study real-time changes in blood flow that are associated with particular tasks and then compared in people with different brain conditions, such as dementia or schizophrenia. Diffusion tensor imaging uses similar technology, but it is not a measure of blood flow; it is a measure of the relative direction of water molecule flow within brain tissue (remember that all of our tissues are mostly made up of water).

Neuronal axons in the brain are wrapped in a fatty tissue layer called a myelin sheath, which gives nerve bundles their characteristic white color, hence the name “white matter. White matter connects different areas of gray matter (where neuronal cell bodies reside). Since axon fiber bundles tend to be organized in a parallel fashion, forming long “cords”, similar to a fiber optics cable, water has a much harder time crossing the “water proof” fatty tissue wrappings of a nerve fiber bundle perpendicular to its axis, and a much easier time flowing along its parallel axis. DTI detects very small differences in water diffusion and is able to calculate the thickness and direction of large white matter tracts in the brain. It is therefore an indirect measure of “connectivity”, the size and organization of the major fiber bundles of the brain.

In this study, the authors recruit 15 right-handed male subjects with SPD and 15 right-handed male control subjects with no psychiatric diagnosis via advertisements in the community – many studies are now trying to match the gender and handedness of their experimental groups, as there is growing evidence that right and left-handed, and male and female brains have small but significant differences in their overall activation patterns. There were no significant differences between the subjects with SPD and the control subjects in terms of age, socioeconomic status, education or IQ.

Most subjects performed a number of written and behavioral tests at the beginning of the study, including measures of SPD symptoms and verbal and visual memory. After the testing period, all subjects were scanned in a magnetic resonance imaging scanner, using a previously standardized DTI technique. This scanning focused particularly on the regions of interest mentioned above, namely the uncinate fasciculus (UF) and the cingulum bundle (CB), two white matter tracts implicated in schizophrenia.

What they found
Diffusion tensor imaging in a MRI scanner measures two primary things: the cross-sectional area (size) of a particular region, and the resistance to water flow in a particular region, an indirect indicator of neural organization. As noted above, the authors of this study had previously implicated the UF and CB as being structurally disorganized in schizophrenia, so they focused their attention on the size and organization of these regions in people with SPD, as compared to people with no psychiatric disorder (“controls”).

The authors found that, like in schizophrenia, the UF showed reduced neural organization in SPD as compared to controls, and this disorganization correlated with certain symptoms and cognitive impairments. Unlike in schizophrenia, however, the CB showed overall no significant difference in white matter organization in SPD vs. controls, though there were some suggestions that some of the subjects with SPD had mild disorganization that correlated with mild deficits in cognitive function – it is a common finding in (expensive) imaging studies that there are not enough subjects to be sure that very small differences are “real” or simply due to normal and expected variation between subjects.

Together, these data support a “continuum” model of psychosis, with SPD sufferers having mildly impaired connectivity in the frontal and temporal lobes of the brain (only the UF being affected) and subsequently only mild symptoms, while people with schizophrenia have more impaired connectivity (UF and CB) and more severe symptoms.

The Take Home Message
It has long been known that schizophrenia often has a “prodromal” period, that is one during which the affected individual suffers a slow, generalized decline in social and cognitive functioning, progressing towards the more frank delusions, hallucinations and disorganized behaviors that are typical of people with the full-blown disorder. Much work has been done in trying to identify people with prodromal symptoms and intervene early in the course of schizophrenia. A perennial problem with studies that try to recruit subjects with prodromal symptoms is the simple fact that the earlier one wants to study the disease course, the less specific the symptoms seen become.

To take social withdrawal and odd beliefs as an example, there are many children and adolescents who will exhibit culturally “strange” behaviors and thoughts about the world that isolate them from most of their peers, but who will never go on to develop schizophrenia. Since SPD shares so many of its symptoms with schizophrenia, it is a common confound in studies that look at prodromal outcomes. This study suggests that it may be possible to perform a simple imaging test that could have predictive value in determining whether someone exhibiting mild symptoms on the schizophrenia spectrum would benefit from anti-psychotics, an important question given the possible side effects of these medications.


Fronto-Temporal Disconnectivity in Schizotypal Personality Disorder: A Diffusion Tensor Imaging Study

Authored by: Nakamura M. McCarley RW, Kubicki M, Dickey CC, Niznikiewicz MA, Voglmaier MM, Seidman LJ, Maier SE, Westin CF, Kikinis R, Shenton ME.
Published in: Biological Psychiatry. 2005 Sep 15;58(6):468-78


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