These findings further confirm white matter pathology associated with heavy prenatal alcohol exposure. The regional findings are in part consistent with our a priori hypotheses in that we observed lower FA in the FASD than control groups in lateral temporal regions and in the vicinity of the lateral splenium of the corpus callosum where we had previously observed dysmorphology in independent samples (Sowell et al., 2001a
). Our findings are somewhat consistent with previous reports of FA differences in FASD in posterior callosal regions (Ma et al., 2005
; Wozniak et al., 2006
) as we found lower FA values localized to more posterior than anterior perisplenial white matter. Previous studies of FA in FASD have evaluated only midsagittal corpus callosum regions of interest, and not whole-brain voxel-based analyses of FA as we have conducted here. Thus, our findings of lower FA values in ILF regions are novel. Results from this study support the hypothesis that higher gray matter thickness in individuals with FASDs in posterior temporal and inferior parietal lobes observed in previous reports (Sowell et al., 2008
) could result from delayed or permanently reduced myelin deposition, at least in the right temporal lobe. In other words, it is possible that tissue with “gray matter” signal on MRI is actually unmyelinated peripheral axonal or dendritic fibers. It is also possible that disorganization of white matter fibers (i.e., fibers with multiple orientations within the same voxel), or lower axonal density could account for the lower FA (Mori and Zhang, 2006
) we observe in the FASD group. It is not clear, however, how disorganization or reduced axonal density of myelinated fibers (which would likely have white matter signal on T1-weighted MRI) could result in higher colocal gray matter thickness values, further implicating dysmyelination rather than disorganization as a cause. Animal or postmortem studies would help further explain the etiology of lower FA and higher cortical thickness associated with heavy prenatal alcohol exposure.
Whatever the microstructural (evaluated with FA analyses) or macrostructural (evaluated with WMD analyses) etiology, abnormalities of FA in some brain regions of the FASD subjects are related to impairment in cognitive functions subserved by those regions. Specifically, lower FA in the lateral splenium and parietal lobe white matter predicted worse performance on a test of visuomotor integration in the FASD group. This finding was specific to FA (and not WMD) in the lateral splenium region, as would be expected given that regions role in visuospatial processing (Cabeza and Nyberg, 2000
), specific to the FASD group, and specific to visuomotor integration (i.e., reading ability was not related to FA values in the splenium region). Thus, these white matter microstructural (i.e., reduced myelination or fiber disorganization) abnormalities in children and adolescents with heavy prenatal alcohol exposure appear to be clinically significant. Our results suggest that this region of white matter is particularly susceptible to damage from prenatal alcohol exposure and that FA in this region may not be variable enough to correlate with VMI performance in the controls. It is also likely that other brain regions not measured in these analyses are related to visuomotor integration in either or both groups.
We also conducted VBM analyses of WMD to evaluate macrostructural white matter differences. Although WMD results were not significant after correction for multiple comparisons, results from the uncorrected analyses suggest a trend toward lower WMD in bilateral lateral splenial and right temporal lobe regions. Lower WMD overlapped with some, but not all voxels significant in the FA analyses. Thus, FA differences between groups cannot be completely mediated by morphological differences in white matter (i.e., comparing white matter tissue in one group to gray matter tissue in another), and must be related to lower myelination or disorganization of white matter fibers. Decreased WMD could also be related to the increased cortical thickness in temporal lobe regions reported previously (Sowell et al., 2008
) given that unmyelinated fibers within the periphery of the cortex may appear as “gray matter” on T1-weighted MRI and may have been included in our gray matter thickness measure in the previous report. Future analyses could involve fiber tractography (Mori and Zhang, 2006
) to define exact fiber tracts within the temporal lobe (i.e., inferior longitudinal fasciculus) in each individual, and group differences in FA within matched tracts could be evaluated (Johansen-Berg and Behrens, 2006
). This type of analysis would help explain observed FA differences caused by mismatched anatomy between groups, and could reveal actual differences in myelination or fiber organization at homologous anatomical structures.
Interestingly, we did not observe wider spread lower WMD measures in the lateral aspects of the temporal lobes in the left hemisphere as we did in a previous report (Sowell et al., 2001b
). It is possible that WMD reductions in the left temporal lobe were subthreshold and at trend level significance in this sample, just as lower FA was in the ROI analyses. It is also possible that differences between the two independent samples accounted for the discrepant results. The previous group we studied tended to be more severely affected than those in the current report with 14 of 21 subjects in the earlier sample having the full FAS diagnosis (Sowell et al., 2001b
) and only 4 of 17 meeting full FAS diagnostic criteria in the current report. We have shown that children with heavy prenatal alcohol exposure but without the facial dysmorphology to obtain the FAS diagnosis have regionally similar, but less severe brain dysmorphology (Sowell et al., 2001a
; O’Hare et al., 2005
). Perhaps the lower proportion of individuals with the full FAS diagnosis in the current report is weakening the observed effects. Unfortunately, with only 4 subjects meeting full FAS diagnostic criteria in this group, statistical power was not sufficient to explain severity effects in the present sample.
We did not confirm lower FA values in the left temporal lobe in the voxel-based analyses. We would have expected similar effects in the left and right hemispheres given bilateral findings of higher gray matter thickness in an independent sample of alcohol-exposed subjects (Sowell et al., 2008
). The post hoc
ROI analyses revealed trend level differences, with lower FA values in the left temporal lobe in the subjects with FASDs. This suggests that greater thickness in the left hemisphere may also be related to disorganization or reduced myelin, although not to the extent that we see in the right hemisphere where FA decreases were statistically significant.
Together, the results presented here strongly implicate white matter microstructural abnormalities in children and adolescents with FASDs, exclusive of relative differences in white matter morphology. Lower FA in the FASD group in lateral splenial/parietal white matter are related to poorer visuomotor integration, although cause-and-effect cannot be derived from such correlational analyses. Whether myelin deposition and organization of white matter fibers is required for intact visuomotor integration, or experience and facility at visuomotor integration result in higher deposition of myelin and organization of fibers is difficult to infer from human studies. Studies of normal childhood and adolescent development show regionally heterogeneous declining cortical thickness, presumably caused by synaptic pruning and greater myelination (for review, see Sowell et al., 2004
). Longitudinal analyses could help in understanding the cascade of events that result in lower FA and WMD in individuals with heavy prenatal alcohol exposure, and whether the insults to the brain are static, or plastic throughout the years of development. Animal studies could also help determine the etiology of white matter abnormalities resultant from prenatal alcohol exposure. Further caveats are warranted regarding difficulties in determining causality of prenatal alcohol exposure in the observed group effects on brain structure and cognitive function given that this is a case-control study and it was not possible to control many other potentially significant differences between the groups (i.e., socioeconomic status among the biological parents of participants with FASDs, prenatal exposure to other drugs in the FASD group) that could be associated with brain and cognitive differences between groups.