Demonstration of in vivo selective brain-behavior relationships, particularly in patients who have diffuse or partial rather than focal or complete brain lesions, is often elusive. Such a condition is alcoholism, in which the characteristic deficits in component processes of executive function, visuospatial function, and balance ( Fein et al. 1990 , Oscar-Berman 2000 , Parsons et al. 1987 , Sullivan et al. 2000 , Tarter and Alterman 1984 ) are probably related to disruption of circuits that link fronto-cerebellar neural nodes ( Sullivan 2003 , Sullivan and Pfefferbaum 2005 ) and provide interhemispheric integration ( Schulte et al. 2004 ) rather than to focal deficits in specific regions. Chronic alcoholism.
Diffusion tensor imaging (DTI) with quantitative tractography provides a powerful tool for assessing the integrity of specific white matter tracks and may be more useful than either quantitative measures of regional brain macrostructure or DTI measures of regional microstructural integrity for demonstrating selective brain-behavior relationships. DTI may be particularly sensitive in the identification of brain substrates of cognitive and motor tasks involving interhemispheric integration in alcoholism and other conditions characterized by partial lesions. A primary measure in DTI is fractional anisotropy (FA), which reflects the extent to which water molecules move in a common restricted orientation in white matter tracts, with higher values representing more consistency, and by implication greater integrity of its microstructural components, such as myelin. Quantitative tractography is a method that extends the use of FA, on an intervoxel basis, to visualize and quantify white matter connectivity, i.e., neural tracts, in the brain.
The corpus callosum, a complex band of white matter fibers linking homologous regions of left and right hemispheres ( Gazzaniga 2005 ), is a key structure for integrating functions between the hemispheres. Interhemispheric connections have been demonstrated postmortem in humans ( Aboitiz et al. 1992 , Gross et al. 1977 , Seltzer and Sherwin 1983 ) and in non-human primates ( Pandya and Seltzer 1986 ). Recent in vivo studies using DTI and white matter FA orientational color maps and fiber tractography ( Abe et al. 2004 , Hofer and Frahm 2006 , Huang et al. 2005 , Park et al. 2007 , Sullivan et al. 2006 ) are consistent with postmortem studies in suggesting that fibers of the genu, the anterior portion of the corpus callosum, connect left and right ventral prefrontal cortex and parts of the dorsal prefrontal cortex, whereas fibers of the splenium, the posterior portion of the corpus callosum, connect bilaterally distributed sites of the temporal, parietal, and occipital cortices ( Pandya and Seltzer 1986 ). Thus, complete or partial lesions at the anterior extent of the corpus callosum could affect the execution of bilaterally distributed executive functions, whereas posterior callosal lesions could affect the transfer of visuospatial information between hemispheres.
Patients with alcoholism have compromised callosal morphology variously described in vivo and postmortem as “,thinning”, or reduced area or volume compared with age-matched controls ( Cardenas et al. 2007 , Estruch et al. 1997 , Harper and Kril 1990 , Hommer et al. 1996 , Lee et al. 2005 , Oishi et al. 1999 , Pfefferbaum et al. 1996, 2006a ). Recent studies quantifying the microstructural integrity of callosal white matter have found DTI to be more sensitive than conventional MRI in detecting callosal compromise in alcoholic women ( Pfefferbaum and Sullivan 2002 ). Other DTI studies of patients with a history of chronic heavy alcohol use have noted a greater predilection for compromised integrity in frontal than posterior callosal regions ( Pfefferbaum and Sullivan 2002 , Pfefferbaum et al. 2000 ). Furthermore, a twin study showed that while genetic influences on regional morphology are similar from anterior to posterior extent, white matter integrity is more susceptible to environmental than genetic influences in the anterior portion than in the posterior portion ( Pfefferbaum et al. 2001 ). DTI thus enhances the ability to differentiate regional sensitivity of the corpus callosum to the environmental toxin of heavy alcohol consumption.
Both macrostructural size and microstructural DTI measures of the anterior genu of the corpus callosum based on a region-of-interest approach have been associated with age or alcohol related impaired performance on several frontally mediated executive tasks, including Trail Making and Symbol Digit tests ( Jokinen et al. 2007 ), episodic memory retrieval time ( Bucur et al. 2007 ), and interhemispheric transfer performance ( Schulte et al. 2005 ). These findings support the functional significance of the topographic organization of the corpus callosum. Few studies ( Pfefferbaum et al. 2007 , Sullivan et al. 2006 ), however, have used quantitative fiber tracking to test for associations and dissociations of selective brain-behavioral relations that reflect interhemispheric integration.
The Digit Symbol (DS) subtest of the WAIS-R ( Wechsler 1981 ) has been widely used as a test of psychomotor performance and visual perception in neuropsychological research and clinical settings because of its sensitivity to brain insult from trauma, neuropsychiatric disease, and environmental toxins including alcohol ( Lezak 1995 ). Patients with alcoholism are commonly impaired on the DS ( Beatty et al. 2000 , Davies et al. 2005 , Harris et al. 2003 , Hochla et al. 1982 , Sullivan et al. 2002a , Sullivan et al. 2000 ), as are many patients with any brain dysfunction. Although DS was not designed as an interhemispheric transfer task, coordination of the executive, visuospatial, motor, and mnemonic processes is required to perform the DS test successfully ( Glosser et al. 1977 , Joy et al. 2000, 2003a, b , Kaplan et al. 1991 ) and likely invokes frontally-based systems and interhemispheric communication. In support of this possibility, we recently reported that executive abilities contributed over and above the contribution of visuospatial, motor, and mnemonic function to prediction of DS scores in patients with alcoholism ( Sassoon et al. 2007 ).
Chronic alcoholism inr
In the present study, we analyzed the contribution of fiber tractography FA of fiber bundles passing through the genu and splenium into their left and right hemisphere cortical targets to performance on the standard DS test. For comparison, we also examined the contribution of these brain measures to performance on an incidental recall test of the symbols. This comparison task was used because it permits examination of a non-frontally based function using the same material as used for the target coordinated psychomotor test. Based on our earlier analysis of factors contributing to DS performance ( Sassoon et al. 2007 ), we tested the hypothesis that integrity of fibers crossing at the genu would contribute more to DS performance than integrity of fibers crossing at the splenium. By contrast, we hypothesized that neither genu nor splenium fiber integrity would contribute selectively to incidental recall.
This study provides evidence for a selective relation between DS performance and fiber tract integrity of the genu of the corpus callosum—,specifically, FA of fiber tracking targeted at the genu predicted coordinated psychomotor performance in chronic alcoholics after accounting for the contribution from FA of fiber bundles coursing through the splenium. This selective relationship demonstrates a predominantly frontal contribution to the DS test, a visually based psychomotor task, requiring speeded eye-hand coordinated actions. By contrast, although genu and splenium of the corpus callosum are reduced in size (based on the size of the target ROIs) in patients with alcoholism, neither region size was associated with performance on the DS test.
Higher FA represents more consistency in water molecule diffusion, and by implication greater integrity of local white matter. The resolution at which these DTI data were acquired, however, precludes direct axonal measurement. Nonetheless, the fibers identified by the tractography software as passing through the genu putatively link the left and right ventral prefrontal cortex and parts of the dorsal prefrontal cortex, whereas fibers passing through the splenium putatively link regions of left and right parietal, temporal and occipital cortices. Thus, a positive association of FA in the genu bundle, reflecting the microstructural integrity of those white matter fibers, with DS performance in alcoholics is consistent with behavioral evidence for a strong executive component to successful DS task performance ( Sassoon et al. 2007 ). Even though FA in splenium fibers showed some association with DS task performance in alcoholics, consistent with the visual scanning and associative learning skills required for this task, it did not contribute independently. Although the DS certainly requires simple psychomotor skills—,tracking and filling in the boxes—,our analysis suggests that performance also benefits from higher order skills, such as directed attention. Performance on the incidental recall task was not impaired in the alcoholic patients and, as predicted, was not associated with either genu or splenium fiber bundle FA. The contrast between fiber tractography and regional size measures as predictors of behavior suggests the possibility that integrity and number of fibers reaching out into the cortical areas from the corpus callosum, rather than size of the section of corpus callosum from which they originate better predict performance.
A limitation of this study is that the DS task was the only behavioral task available across this entire subject sample with which to assess the functional ramifications of impaired white matter fiber integrity in genu and splenium of the corpus callosum. The two measures yielded by this task—,number of boxes completed in 90 s and score on incidental recall of the symbols—,were, nonetheless, successful in showing differential associations with genu and splenium.
As expected, and regardless of diagnosis, women as a group performed the DS test better than men ( Snow and Weinstock 1990 ), but there was no evidence to suggest that group differences in performance were an artifact of the fact that there were a larger proportion of women in the control sample than in the alcoholic sample. Furthermore, among the alcoholics, similar patterns of association between DS performance and genu fiber FA were observed in both men and women, albeit with a stronger effect in the larger sample of men.
Functional ramifications of the topographic organization of the corpus callosum in humans have been studied by administering cognitive tests to patients with callosal lesions resulting from relatively discrete trauma (e.g., Peru et al. 2003 ) to more extensive surgically induced lesions (e.g., Funnell et al. 2000 , Gazzaniga 2005 ). Such studies have illuminated complex patterns of interhemispheric communication as well as compensatory mechanisms that develop when the normal functional connections either fail to develop or are damaged. Recent brain imaging studies using DTI are revealing not only the integrity of the corpus callosum and its classically defined subsections, but are redefining those sections in terms of the source and target of white matter fiber tracts that course through them ( Hofer and Frahm 2006 ). The application of quantitative tractography also permits the investigation of incomplete lesions in the corpus callosum, such as those associated with chronic alcohol use, and provides evidence that impaired integrity of white matter tracks coursing through the genu, the anterior portion of the corpus callosum, contributes to impaired performance on tasks such as the DS that rely on interhemispheric coordination of frontal lobe processes. As new analysis approaches permit greater specificity in identifying and quantifying the integrity of white matter circuits linking not only left and right hemispheres but also cortical-subcortical and anterior-posterior circuits they will allow further investigations of the neural underpinnings of a wide range of cognitive processing.
Margaret J. Rosenbloom, Neuroscience Program, SRI International, Menlo Park, CA, USA. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305-5723, USA.
Stephanie A. Sassoon, Neuroscience Program, SRI International, Menlo Park, CA, USA.
Rosemary Fama, Neuroscience Program, SRI International, Menlo Park, CA, USA.
Edith V. Sullivan, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305-5723, USA.
Chronic alcoholism heart failure
Adolf Pfefferbaum, Neuroscience Program, SRI International, Menlo Park, CA, USA. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305-5723, USA.