Tract-based spatial statistics (TBSS) of diffusion tensor imaging data in alcohol dependence: Abnormalities of the motivational neurocircuitry
Introduction
Water diffusion in the brain is influenced by the local microstructure of the tissue. Magnetic resonance diffusion tensor imaging (DTI) is a quantitative non-invasive and objective method for assessing the integrity of major white matter (WM) fiber tracts indirectly via measurement of the directionality of water diffusion (fractional anisotropy, FA) (Pierpaoli and Basser, 1996). FA reflects axonal diameter, axonal density and fiber tract complexity (Beaulieu, 2002). Water diffusion or mobility in WM is mainly hindered by myelin sheaths and cell membranes (Beaulieu, 2002) so that its movement is influenced by level of myelination and axonal density. More specifically, reduced FA can be attributed to degradation of both myelin sheaths and axonal membranes (Werring et al., 2000, Pierpaoli et al., 2001), abnormalities of myelin with sparing of the axonal fibers (Gulani et al., 2001, Song et al., 2002), or reduced density of axonal fibers (Takahashi et al., 2002). Mean diffusivity (MD), which is the overall mean-squared displacement of water molecules restricted by organelles and membranes (Neil et al., 1998), reflects cellular density and extracellular volume (Gass et al., 2001, Sotak, 2004) and relates to the volume fraction of the interstitial space (Sotak, 2004). Thus, low FA and high MD in the same brain region indicate higher intracellular or extracellular fluid associated with less organized myelin and/or axonal structure (Pfefferbaum and Sullivan, 2005). The spatial orientation of fibers can be derived from the eigenvalues from the diffusion tensor, and parallel (λ1) and perpendicular (λ2 and λ3) diffusion to the WM tract can be calculated; these are also referred to as axial diffusivity, λ|| = λ1, and radial diffusivity, λ⊥ = (λ2 + λ3)/2.
The hydrophobic myelin sheath hinders water movement perpendicular to axonal tracts (λ⊥), imposing a preferential diffusion direction parallel (λ||) to the WM tracts (Klingberg et al., 1999, Harsan et al., 2006). Therefore, an increase of λ⊥ is thought to signify increased space between fibers (suggesting demyelination or dysmyelination) (Song et al., 2003, Harsan et al., 2006), whereas a decrease in λ|| suggests axonal injury (Ito et al., 2002, Lazar et al., 2003).
In alcohol use disorders (AUD = alcohol abuse or dependence), microstructural WM integrity is thought to be disrupted by both demyelination and axonal structural abnormalities (Pfefferbaum and Sullivan, 2002, Pfefferbaum and Sullivan, 2005, Pfefferbaum et al., 2006a, Pfefferbaum et al., 2006b). These changes can be permanent or transient (Carlen et al., 1984). Permanent injury is thought to involve neuronal death with secondary axonal (Wallerian) degeneration, which has been documented in superior frontal lobe, hypothalamus and cerebellum (for review, see Oscar-Berman, 2000, Sullivan, 2000). Morphological abnormalities in AUD include transient changes and may include shrinkage of neuronal soma, dendritic pruning, decreased axonal size and density as well as myelin changes, which are manifested on magnetic resonance (MR) neuroimaging as reductions in brain tissue volume, metabolite abnormalities and decreased cerebral blood flow (Sullivan, 2000). Volumetric abnormalities may show partial to substantial recovery during short-term or extended sobriety (e.g., Pfefferbaum et al., 1995, Gazdzinski et al., 2005, Yeh et al., 2007). However, AUD-related microstructural abnormalities have been observed in regions of WM that appear grossly normal on structural MRI (Sullivan and Pfefferbaum, 2003). For example, FA reductions were reported in the genu of the corpus callosum (cc) and the centrum semiovale (cs) that exhibited no gross lesions on standard structural images (Pfefferbaum et al., 2000, Pfefferbaum and Sullivan, 2002, Pfefferbaum and Sullivan, 2005, Pfefferbaum et al., 2006a, Pfefferbaum et al., 2007).
Recent research in AUD has focused on the brain reward circuitry, which is implicated in the development and maintenance of substance use disorders in general (Chambers et al., 2003, Sullivan et al., 2003, Kalivas and Volkow, 2005, Sullivan and Pfefferbaum, 2005, Sullivan, 2003, Bowirrat and Oscar-Berman, 2005). This network is composed of dopaminergic afferents, which originate in the ventral tegmental area of the midbrain and project to the nucleus accumbens, prefrontal cortex, limbic, and striatal structures, and of reciprocal GABAergic or glutamatergic circuits connecting the dorsal anterior frontal cortex, orbito-frontal cortex, anterior cingulate cortex, and ventral striatum.
Current DTI data analysis methods, which include voxelwise analysis, region-of-interest (ROI) analysis, and tractography, suffer from the low spatial precision of cross-subject image alignment, the residual misalignment due to group differences in ventricular size, and the lack of knowledge of the proper degree of spatial smoothing. Additionally, traditional linear affine transformations may result in geometric tract distortion upon coregistration of WM tracts between groups. Tract-Based Spatial Statistics (TBSS), which uses nonlinear image transformation, is a newly developed technique that combines the strength of both voxelwise and tractography-based analyses (Smith et al., 2006). In this report, we demonstrate the application of TBSS to the investigation of the voxelwise differences of diffusion measures between alcohol-dependent individuals (ALC) and non- or light-drinking controls (LD). The goals of this study were 1) to implement TBSS of DTI data in ALC, 2) to describe and measure potential microstructural differences in the motivational neurocircuitry of ALC and LD, and 3) to correlate measures of drinking severity and neurocognition to the DTI measures of local WM microstructural abnormalities in ALC.
Section snippets
Methods
All study participants were recruited as part of a larger magnetic resonance (MR) neuroimaging and cognition study to measure the effects of chronic drinking and smoking on the brain. Treatment-seeking alcoholics (ALC) were recruited from the Substance Abuse Day Hospital at the San Francisco Veterans Administration Medical Center and the San Francisco Kaiser Permanente Chemical Dependence Recovery Program, whereas light drinking controls (LD) were recruited by word-of-mouth and from the
Group comparisons
Table 1 summarizes major results from analyses that used permutation testing for group comparisons and FDR (5%) for correction of multiple comparisons. Listed are the brain locations of significant voxels, the names of the major fiber tract, the maximal t-values of a cluster and its size, as well as the position of the maximal t-values in MNI space. Significance was thresholded at P < 0.05 with a cluster of at least 200 isotropic voxels. Table 2 summarizes the results obtained from group
Discussion
This TBSS analysis of DTI data from alcohol-dependent individuals reveals widespread injury to WM regions including major fiber tracts in the frontal lobe, mesial temporal lobe, and cortico-striatal regions. FA decreases in deep WM regions are generally due to increased λ⊥, whereas MD increases in more subcortical WM regions are generally associated with higher λ||. In ALC participants, reduced FA in regions of major commissural fibers and association fibers of the corona radiata and superior
Acknowledgements
NIH AA10788 (DJM) and the Veteran's Administration research service supported this project. We thank Mary Rebecca Young and Bill Clift of the San Francisco VA Substance Abuse Day Hospital, and Dr. David Pating, Karen Moise, and their colleagues at the San Francisco Kaiser Permanente Chemical Dependency Recovery Program for their valuable assistance in recruiting research participants. We also thank Dr. Hemanth Thayyullathil for assistance with data analyses, as well as Drs. Michael W. Weiner,
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