In this Turboprop DTI study, as predicted, we observed lower prefrontal fractional anisotropy localized to right uncinate fasciculus (UF) white matter in the area adjacent to the orbitofrontal cortex in individuals GSAD compared to matched healthy controls. Anatomically, the UF is the major WM fiber tract that connects the inferofrontal and anterotemporal cortices, and it travels over the lateral nuclei of the amygdala terminating in the OFC (Brodmann area 11-12) and subcallosal area (Brodmann area 25) (9
). Thus, lower FA within this tract suggests aberrant fronto-amygdala structural connectivity in GSAD. Given that subcallosal frontal regions, such as the OFC, serve important roles in top-down regulation of amygdala reactivity to control negative affect (i.e., anxiety) and mediate threat perception (6
), this UF white matter tract is suggested to play a key role in emotional responding (24
). This is consistent with evidence from functional neuroimaging studies implicating aberrant reactivity in amygdala to social threat and scrutiny in GSAD (2
), and thus abnormalities in UF which carries the most prominent fibers between these two regions may explain why differential reactivity exists. This finding is consistent with recent functional neuroimaging studies have implicated the OFC in social anxiety disorder (25
). Moreover, the Cohen d
(0.63) suggests a small to medium size effect, and is consistent with other studies of uncinate fasciculus abnormalities in bipolar disorder (27
) and of frontal white matter in schizophrenia (28
There is no prior study of WM integrity as measured by DTI in social phobia to use for comparison, however, recent DTI studies have shown that reduced uncinate fasciculus FA is associated with lower levels of extraversion and fewer friends (29
) and higher levels of suspiciousness and interpersonal difficulties (30
) in schizotypal personality disorder. Moreover, an association between uncinate fasciculus FA and impulsivity and aggression in schizophrenia has previously been observed (31
). Therefore, reductions in FA within the uncinate fasciculus may not be specific to social anxiety disorder, given similar findings are observed in bipolar disorder and schizophrenia (27
). Therefore, we speculate that altered FA in this white matter tract that connects amygdala to OFC, both of which also have been similarly implicated across these disorders, may reflect a common phenotype such as affect dysregulation and/or impaired social interactions.
The reduction in FA was due to an increase in secondary and tertiary eigenvalues which could be attributed to any or all of the following processes: 1) decrease in axonal density; 2) decrease in axonal myelination; 3) abnormal axonal membranes; and/or 4) reorganization of axons at a macroscopic level (11
). Moreover, our findings of UF tract abnormalities do not allow inferences about directionality; DTI cannot distinguish unidirectional or bi-directional loci of abnormality. Nevertheless, the difference in GSAD subjects in orbitofrontal white matter integrity may help explain the observed abnormalities in OFC and/or amygdala function in GSAD. Interestingly, recent studies have demonstrated a correlation between fMRI BOLD activation measures (as indexed by blood oxygenation) or electrophysiological changes (as indexed by event-related potentials) and fractional anisotropy (34
), suggesting that the observed hyper-reactivity in amygdala and/or OFC or aberrant ‘functional’ connectivity of these regions may be related to FA measures in WM tracts that connect these regions. Future studies are needed to directly investigate this interpretation.
It should be noted that the observed finding of group differences in UF nearby the OFC would not have survived correction for multiple comparisons, raising the concern for Type I error. As noted above, this is less likely given that OFC dysfunction has been demonstrated in GSAD and that a cluster size (>100 mm3
) was set. Correction for multiple comparisons across all voxels of the whole-brain search volume using Gaussian random field theory has been argued as undesirable because it necessitates the use of smoothed data which results in loss of anatomical information (31
), and other conservative approaches such as permutation testing and false discovery rate analyses substantially reduce statistical power. Because we conducted a whole-brain voxel-wise analysis, the problem of multiple comparisons and an increased risk of a type I error remain and it should be noted that we were only able to detect differences in FA maps using a liberal threshold, and this does reduce the strength of the conclusions of the study and prompts caution in interpreting these preliminary results. The observation that the size of the current sample of unmedicated GSAD patients without current/active depression and substance abuse (n=30) yielded a relatively focal WM finding of small to moderate effect size may help guide future studies.
In summary, based on findings of altered fractional anisotropy as measured by diffusion tensor imaging, the current study presents preliminary evidence of a white matter abnormality within the uncinate fasciculus, the most prominent fiber tract linking the amygdala and orbitofrontal cortex, in individuals with GSAD. This finding may reflect or explain the aberrant patterns of amygdala, frontal, or their interactions in response to social threat in this disorder, and prompt further studies on white matter pathology in disorders associated with social anxiety and interpersonal difficulties.