More Is Not Always Better: Increased Fractional Anisotropy of Superior Longitudinal Fasciculus Associated with Poor Visuospatial Abilities in Williams Syndrome

Abstract

We used diffusion tensor imaging to examine white matter integrity in the dorsal and ventral streams among individuals with Williams syndrome (WS) compared with two control groups (typically developing and developmentally delayed) and using three separate analysis methods (whole brain, region of interest, and fiber tractography). All analysis methods consistently showed that fractional anisotropy (FA; a measure of microstructural integrity) was higher in the right superior longitudinal fasciculus (SLF) in WS compared with both control groups. There was a significant association with deficits in visuospatial construction and higher FA in WS individuals. Comparable increases in FA across analytic methods were not observed in the left SLF or the bilateral inferior longitudinal fasciculus in WS subjects. Together, these findings suggest a specific role of right SLF abnormality in visuospatial construction deficits in WS.

The Williams syndrome chromosome 7q11.23 hemideletion confers hypersocial, anxious personality coupled with altered insula structure and function

“…Such vulnerabilities may lead to malformations in transmodal nodes, and their connections, during critical developmental periods of cortical organization. Our present findings of alterations in the uncinate fasciculus, along with previous demonstrations of abnormalities in white-matter tracts connecting other transmodal regions in WS (25,26), provide support for this proposed neurogenetic mechanism.…”

“…Indeed, we previously reported (25) a relationship between DTI measures and IQ in WS, highlighting the importance of selecting diagnostic groups matched by IQ, as we did here. Moreover, abnormalities found in our high-functioning group are likely to also be present in individuals with WS with intellectual impairment [as has been demonstrated in previous studies (26,28,54)], but nonspecific aspects of brain structure and function associated with intellectual impairment will not be represented in our cohort. Therefore, the neurobiological phenotype reported here is likely to be proximal to the genetic substrate of the disorder, rather than to intellectual impairment per se, consistent with our overall objective of using neuroimaging to forge a link between the effects of specific genes and brain mechanisms of cognitive and behavioral disorders.…”

“…In line with these gray-matter findings, we also detected compromised white-matter integrity (i.e., reduced FA) in the left uncinate fasciculus. Given the role of the uncinate fasciculus in relaying synaptic information between the frontoamygdalar system and the AI (26)(27)(28), this compromised amygdala-OFC white-matter connectivity via the AI, along with our findings of negative functional rCBF coupling of right vAI with OFC and dorsal insular subregions, provides direct anatomical and functional support for previous findings of disrupted functional fronto-amygdala connectivity in WS during processing of emotions (17,28). These results are consistent with neuroanatomical evidence suggesting marked rightward asymmetry of this system in normal subjects (35,42).…”

“…These include the hippocampal formation, IPL, amygdala, and OFC (12,14,17,20,(23)(24)(25)(26)(27)(28)30). Such transmodal cortical systems (51) are composed of subregionally specialized and highly interconnected heteromodal, paralimbic, and limbic cortices (51)(52)(53).…”

“…These mouse studies also documented alterations in fear response [for both LIMK1 and GTF2IRD1 (20,22)] and reduced aggression [for GTF2IRD1 (22)]. In parallel with these preclinical observations, research on the neural mechanisms underlying WS-specific behavioral characteristics has identified functional and structural alterations of the intraparietal sulcus (12,(23)(24)(25)(26), hippocampal formation (27), amygdala, and orbitofrontal cortex (OFC) (12,17,28), and aberrant orbitofrontal circuitry has been associated with the syndrome's distinctive pattern of emotional processing: remarkable lack of social fear coupled with a high incidence of nonsocial anxieties and phobias (17,29,30).…”