Schizophrenia is a serious and disabling mental disorder that affects approximately 1% of the general population, with often devastating effects on the psychological and financial resources of the patient, family, and larger community. It generally afflicts individuals in early adulthood, at a time when they are on the threshold of entering the most productive and formative years of life. The overt, or positive, symptoms of the disorder include auditory hallucinations, disordered thinking, and delusions, while the negative symptoms include avolition, anhedonia, blunted affect, and apathy. Additionally, broad areas of functioning are frequently disturbed including attention, memory, emotion, motivation, thought and language processes, social functioning, and mood regulation.
The etiology of schizophrenia is not known, although it likely involves several interacting biological (e.g., genetic and neurodevelopmental) and environmental factors (e.g., viral infection, fetal insult, drug abuse) that predispose an individual to schizophrenia. Of note, however, although the underlying pathology remains unknown, both Kraepelin1
(pioneers of schizophrenia) believed that brain abnormalities would ultimately be linked to the etiology of schizophrenia. This theory was rekindled in the 1970s, when the first computer-assisted tomography (CT) study showed enlarged lateral ventricles in schizophrenia.3
With the introduction of magnetic resonance imaging (MRI) studies, the first MRI study of schizophrenia was conducted in 1984.4
Since that time, there have been many improvements in MR acquisition and image processing, including the introduction of positron emission tomography (PET), followed by functional MR (fMRI) and diffusion tensor imaging (DTI), all of which have enabled us to exploit more fully information contained in MR and other medical images. These advances have led to an appreciation of the critical role that brain abnormalities play in schizophrenia.
MRI findings in schizophrenia include lateral ventricle enlargement, medial temporal lobe volume reduction (including amygdala-hippocampal complex and parahippocampal gyrus), neocortical superior temporal gyrus volume reduction, frontal and parietal lobe abnormalities, and subcortical abnormalities affecting the cavum septi pellucidi, basal ganglia, corpus callosum, thalamus, and cerebellum (see review in ref. 5
). These findings further suggest the involvement of a large number of functionally related brain regions. Of note here, Wernicke6
both suggested that schizophrenia might be a disease of insufficient or ineffective communication between these brain regions. This hypothesis has been refueled by recent functional imaging studies, which have demonstrated functional connectivity abnormalities between temporolimbic and prefrontal regions (e.g., refs. 7–11
). These findings, as well as recent postmortem and genetic studies that demonstrate myelin-related abnormalities in schizophrenia,12–14
suggest that not only functional, but also anatomical disconnection between brain regions may be involved in schizophrenia. This latter speculation has led to an interest in investigating white matter fiber tract abnormalities in schizophrenia. Here, the focus is on long, association fiber tracts, consisting of heavily myelinated axons, which interconnect distant brain regions. Of particular interest, and based on earlier speculations, are white matter fiber tracts connecting the frontal and temporal lobes.
Finally, while structural MRI has proven to be useful in investigating and detecting gray matter abnormalities in schizophrenia, the investigation of white matter has proven to be more challenging as white matter appears homogeneous on conventional MRI and the fibers connecting different brain regions cannot be appreciated. With the development of diffusion tensor imaging (DTI), we are now able to investigate white matter abnormalities in schizophrenia.