Multiple lines of evidence suggest that microstructural abnormalities in the white matter are important in the pathophysiology of schizophrenia. Diffusion MRI approaches which can provide evidence on tissue structure have been widely used to probe these abnormalities in vivo, but transverse relaxation times (T2) may provide additional insights since they are determined by molecule–microenvironment interactions not revealed by diffusion MRI. T2 of water – located both intra and extracellularly – and N-acetylaspartate (NAA — located intracellularly) reflect related but distinct processes due to their differential localization and interactions with other molecules. In this study, we collected water and NAA T2 data from 16 healthy subjects (HC), and 16 patients with schizophrenia (SZ) at 4 T in a 9 cm3 voxel in the right prefrontal white matter. The SZ group had longer water but shorter NAA T2 relaxation times when compared with the HC group. This pattern resulted in a statistically significant metabolite × group interaction (F(18,1):4.980, p = 0.039). Prolongation of water T2 and shortening of NAA T2 is consistent with an impoverishment of white matter macromolecule structures (including myelin) and abnormal intra-axonal milieu and volume in SZ.
Several lines of evidence suggest that integration of activity across brain regions is as important as processing within any one brain region both for normal cognition and in the pathophysiology of schizophrenia (SZ). Related abnormalities in SZ include abnormally low correlations in resting-state BOLD fMRI signal across remote brain regions (Garrity et al., 2007, Williamson, 2007 and Whitfield-Gabrieli et al., 2009), abnormalities in white matter (WM) integrity (Kubicki et al., 2007 and Camchong et al., 2009), and in expression of myelin- and oligodendrocyte-related genes (Tkachev et al., 2003) required for WM formation and maintenance. WM abnormalities are critical to conceptualization of SZ as a dysconnection (i.e. abnormal connection) syndrome ( Paus et al., 2008 and Stephan et al., 2009). Diffusion MRI, and diffusion tensor imaging (DTI) in particular, have been used to probe WM abnormalities in SZ.
Magnetic resonance spectroscopy (MRS) can provide an additional window to the brain's cellular microenvironment through the measurement of transverse relaxation times (T2) of neurometabolites. Transverse relaxation is a result of nuclear spin–spin interactions reflected in MRS signal decay as echo time (TE) increases, and is sensitive to changes in molecular motion mainly through interactions of small molecules (metabolites) with structural or cytosolic macromolecules. T2 measurements convey valuable neurobiological information. For example, there is a dramatic reduction in brain water T2 during early postnatal brain development as water molecules increasingly interact with rapidly proliferating macromolecules (lipid membranes, myelin components, cytosolic proteins) (Kreis et al., 1993). T2 of major brain metabolites likewise reflect their differential tissue distribution and local molecular interactions during development and adult life (Frahm et al., 1989, Hetherington et al., 1994 and Posse et al., 1995). Thus, T2 provides a glimpse into the frequency of interactions between a molecule and its microenvironment. This can be due to geometric changes within the cell (atrophy) or to the entrapment of a molecule in a larger molecular assembly (e.g. enzyme or transport molecules).
Brain water T2 relaxation times are prolonged in patients with SZ, particularly in frontal and temporal gray matter (Andreasen et al., 1991 and Williamson et al., 1992), and fornix (Supprian et al., 1997). One study showed that this prolongation extends into both gray and white matter (Pfefferbaum et al., 1999). By contrast, T2 of MRS-visible intracellular metabolites such as N-acetylaspartate (NAA), Creatine (Cr), and Choline (Cho) have not been widely studied in psychiatric conditions. We recently reported reductions in T2 measures of these metabolites in bipolar disorder and schizophrenia in two gray matter regions (Ongur et al., 2010). This pattern of prolonged water T2 coupled with shortened metabolite T2 suggests that psychiatric disorders are associated with neuronal and/or glial abnormalities, specifically an impoverished macromolecule compartment and reduced cell size and density. There are currently no studies, however, that have quantified water and metabolite T2 in the same patient cohorts; this would provide compelling evidence for microstructural abnormalities in SZ.
In this study, we quantified WM water and metabolite T2 simultaneously using 1H MRS from a new cohort of patients with chronic SZ taking medication and new healthy controls (HC) matched for age, sex, and parental socioeconomic status at 4 Tesla (4 T). WM abnormalities are widely reported subjacent to the PFC in SZ and may be implicated in its pathophysiology (Camchong et al., 2009) but the microstructural basis of these abnormalities has not been fully elucidated. Therefore, we collected data from a 9 cm3 WM voxel underlying the right prefrontal cortex (PFC). Given the design of our study, we had time to collect data from a single voxel in the white matter. We focused on the right hemisphere in order to avoid the potential for language-related variability in the left hemisphere. Based on the literature reviewed above, we hypothesized that SZ patients would have longer water and shorter metabolite T2 when compared with healthy controls. Because we report both water and metabolite data, we focused on NAA as the metabolite of interest for clarity. The Cr and Cho data were similar, as discussed below.
