Tract-based analysis in schizophrenia: measuring structure and function along white matter tracts

Abstract

Schizophrenia is a severe psychiatric disorder that is characterized by hallucinations, delusions, thought disorder and impairments in cognitive functions. From about the time of its definition it was suggested that schizophrenia is a connectivity disease. Although the etiology of schizophrenia is still not known, recently evidence is accumulating that the integrity of white matter fibers is compromised in schizophrenia and that impaired functioning of white matter is part of its pathophysiology. Modern magnetic resonance imaging (MRI) methods such as diffusion tensor imaging (DTI) in combination with fiber-tracking algorithms allow us to reconstruct these fiber bundles and to study several aspects of these bundles in detail. Structure and function of white matter fiber bundles were studied in both healthy participants and in schizophrenia patients using a novel technique named tract-based analysis. With this type of analysis groups are compared at the level of complete fiber bundles. The average fractional anisotropy (FA) and magnetization transfer ratio (MTR) were measured along the genu of the corpus callosum and the left and right uncinate fasciculus (UF) in 40 schizophrenia patients and 40 healthy participants. These fiber bundles connect to the frontotemporal gray matter regions and are expected to be involved in schizophrenia. A significant negative correlation was found between age and mean FA in the left UF in patients but not in healthy participants which may be more prominent in patients with longer illness duration. The main finding was a significant increase in MTR of 1% in the right UF in patients compared to healthy participants. This increase in MTR in the right UF could reflect a compensatory role for myelin in these fibers or possibly represent aberrant frontotemporal connectivity. Moreover, DTI was combined with resting-state fMRI to determine whether there is a relation between the level of resting state of the precuneus and the posterior cingulate cortex, gray matter regions part of the default-mode network, and the “strength” (reflected by FA) of the connecting fiber bundle. DTI and resting-state fMRI scans of 45 healthy participants were acquired. A significant positive correlation was found between the mean FA value and the level of resting-state suggesting a direct relationship between structural and functional connectivity in the default-mode network. Importantly, a new method -which we dubbed functional diffusion tensor imaging (fDTI - was introduced which is based on tract-based analysis and allows to study functional aspects of fiber bundles. In a first study 8 subjects were scanned during repetitive visual and tactile stimulation. Fiber activation was found as expected in the contralateral thalamocortical tract and optic radiations for tactile and visual stimuli, respectively. These findings were successfully replicated in a second study a using the same stimuli but in a different group of 12 subjects, with a different scanner and an improved fDTI acquisition. The successful application of tract-based analysis to study various aspects of white matter suggests a prominent role for tract-based analysis in studying diseases for which white matter may be implicated, in particular schizophrenia.