“Schizophrenia was once dubbed the ‘graveyard for neuropathologists,’” says Dr. Thomas Whitford. “The changes in brain structure that accompany the disease are subtle in comparison to the severity of patients’ symptoms. In light of this, a prevailing theory of schizophrenia emphasizes the role of abnormal neural communication or connectivity, in addition to altered localized brain structure in the etiology of the disease.” A recent study by Whitford and colleagues provides strong evidence that schizophrenia is associated with subtle changes in white-matter volume, evidence that supports the neural connectivity model of schizophrenia.
Connectivity
“One of the cardinal features of schizophrenia is known as cognitive disorganization,” notes Dr. Whitford. “People with schizophrenia often make unusual associations in their thoughts and language—associations that people without schizophrenia wouldn’t make. This raises the question of whether these unusual connections between ideas are underpinned by aberrant physical connections in the brain. Alternatively, perhaps there is an abnormality in neural timing such that normally precisely-timed neural signals arrive too early or too late. An increasingly popular model of schizophrenia argues that such an abnormality in neural connectivity underlies not only the cognitive disorganization associated with the disease, but also the more ‘florid’ symptoms of psychosis such as hallucinations and delusions.”
Furthermore, as Dr. Whitford explains, the “negative” symptoms in schizophrenia can also be explained by the connectivity model. “It is possible to imagine that a signal sent at slightly the wrong time or to slightly the wrong place could lead to a disorganization of thought and an attempt by the brain to rationalize the disorganized thought, which could form the basis of a delusion. However, it is also possible to imagine that beyond a certain point the disjunction becomes too great and the brain is simply not able to integrate the disordered thoughts anymore and instead ‘freezes up,’ perhaps rather like a computer freezes when attempting to perform too many buggy operations at once. This ‘freeze’ would be associated with the negative symptoms of avolition, alogia, apathy and general cognitive slowing.”
White Matter
Prior to Dr. Whitford’s recent study, evidence implicating white matter irregularity in schizophrenia was sparse. “White matter is the infrastructure for all but the shortest-distance communication in the brain,” Dr. Whitford says. “The white matter connects disparate areas of the cortex and lower brain structures, so it is fundamental to neural connectivity. Despite its importance, however, it’s been very difficult to study.”
Previous attempts to use MRI to examine white matter volume in the brain have been thwarted by the undifferentiated nature of white matter. Unlike other parts of the brain, there are few referential landmarks in the white matter, making it difficult to define consistent regions of interest in different brains.
“We got around this problem by using a computerized analysis technique known as voxel-based morphometry,” Dr. Whitford explains. “Essentially, this involves breaking the brain images into thousands of tiny cubes and calculating the volume of white matter in each of them. This allowed us to identify small regions of volumetric difference in the white matter across brains.”
Whitford and colleagues found that patients experiencing their first episode of schizophrenia, in the very early stages of illness, had reductions of white matter volume in the frontal and parietal lobes, as well as a few regions where the patients had higher white matter volume compared to those without schizophrenia. “We then scanned these patients again, 2–3 years later, and we found that they had lost a greater amount of white matter in the temporal region than had healthy comparison participants. This is clear evidence for progressive degeneration occurring at least at some period over the first few years of the illness.”
Applications
According to Dr. Whitford, “The fact that white matter abnormalities present so early in the course of schizophrenia raises the question of whether they actually occur prior to the onset of psychosis, and whether it might be possible to therefore predict which people will go on to develop schizophrenia. The ability to predict ahead of time which people will develop psychosis could potentially lead to the development of preventative treatments, which is really the holy grail in this sort of research. It would open the door for the use of prophylactic antipsychotic medications and might also mean that we’d have a better chance of dissuading high-risk people from taking part in risky behaviors which might trigger psychosis, particularly the use of recreational drugs such as crystal methamphetamine.”
Future Directions
“We found evidence of progressive white matter atrophy occurring at some point over the first 2-3 years of our patients’ illness—the next big question, then, is, does this atrophy continue on for longer?” says Dr. Whitford. “The possibility that schizophrenia could be a neurodegenerative disease has interesting implications. However, it is not possible to conclude on the basis of this study whether or not schizophrenia is a neurodegenerative disease, as the white matter atrophy we found could be temporally localized in the first year or so after the onset of disease. If we could scan these participants again in 5 years, and then 5 years after that and so on, and examine the pattern of white matter changes, then we’d have a much clearer picture. If progressive atrophy is actually a defining characteristic of schizophrenia, this would suggest a whole new approach to understanding and treating the disease.”
Acknowledgements & Financial Disclosures: This work formed part of Dr. Thomas Whitford’s PhD project, which was undertaken through the University of Sydney and supervised by Associate Proffesor Lea Williams, Dr. Anthony Harris and Dr. Tom Farrow. Dr. Harris has received research funding from Organon Australia and Janssen Cilag Australia; he has also received educational or advisory board fees from Eli Lilly, Bristol-Myers Squibb, and Wellmark. Dr. Gordon is CEO of the Brain Resource Company. Dr. Williams is supported by a Pfizer senior research fellowship, which is a peer reviewed fellowship, administered by an independent research trust board; she is also a minor shareholder in the Brain Resource Company. Dr. Grieve has been employed by the Brain Resource Company, but his employment was independent from this research. Drs. Whitford, Farrow, Gomes and Brennan report no competing interests. The Research Trust Fund of the Schizophrenia Fellowship of NSW, the Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD), and the NSW Department of Health provided support for the Western Sydney First Episode Psychosis project.
