Functional neuroanatomy of visuospatial working memory in fragile X syndrome: Relation to behavioral and molecular measures

Objective: Fragile X syndrome is a neurogenetic disorder that is the most c ommon known heritable cause of neurodevelopmental disability. This study ex amined the neural substrates of working memory in female subjects with frag ile X syndrome. Possible correlations among behavioral measures, brain acti vation, and the FMR1 gene product (FMRP expression), as well as between IQ and behavioral measures, were investigated. Method: Functional magnetic resonance imaging was used to examine visuospat ial working memory in 10 female subjects with fragile X syndrome and 15 typ ically developing female subjects (ages 10-23 years). Subjects performed st andard 1-back and 2-back visuospatial working memory tasks. Brain activatio n was examined in four regions of the cortex known to play a critical role in visuospatial working memory Correlations between behavioral, neuroimagin g, and molecular measures were examined. Results: Relative to the comparison group, subjects with fragile X syndrome performed significantly worse on the 2-back task but not on the 1-back tas k. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, co mparison subjects showed significantly increased brain activation between t he 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. Significant correlations were f ound in comparison subjects between activation in the frontal and parietal regions and the rate of correct responses on the 2-back task, but not on th e 1-back task. In subjects with fragile X syndrome, significant correlation s were found during the 2-back task between FMRP expression and activation in the right inferior and bilateral middle frontal gyri and the bilateral s upramarginal gyri. Conclusions: Subjects with fragile X syndrome are unable to modulate activa tion in the prefrontal and parietal cortex in response to an increasing wor king memory load, and these deficits are related to a lower level of FMRP e xpression in fragile X syndrome subjects than in normal comparison subjects . The observed correlations between biological markers and brain activation provide new evidence for links between gene expression and cognition.