ABSTRACT

Fragile X syndrome is the most common inherited cause of neurodevelopmentaldisability, occurring at a frequency of approximately one inevery 2,000 to 4,000 live births.1 The syndrome arises fromdisruption in expression of the FMR1 gene, which is most commonlycaused by expansion of a CGG repeat stretch in the gene, withresultant methylation and silencing of expression. The absenceof the FMR1 gene product (FMRP) in neurons is associated withabnormal morphology of dendritic spines and a reduction in thelength of synapses in the cortex.2,3 The neuropsychologicalprofile of fragile X syndrome is notable for mental retardation,as well as difficulties in visual memory and perception, mentalmanipulation of visuospatial relationships among objects, visual-motorcoordination, processing of sequential information, and executivefunction.4-6 In this study, we used a working memorytask to investigate deficits in higher-order cognition in subjectswith fragile X syndrome. Impairment in visuospatial workingmemory may be an important contributing factor to the behavioralprofile of people with fragile X syndrome. For example, impairmentin the processing and retention of information in social situations,an area of cognition known to be heavily dependent on nonverbalskills, may be implicated in difficulties known to occur insubjects with fragile X syndrome, such as poor social relatedness, avoidance, and anxiety.7-9

Working memory is the ability to hold and manipulate informationonline in the brain.10-12 The component processes involvedin working memory —encoding, rehearsal, storage, and executiveprocesses on the contents of stored memory-represent keycognitive operations of the human brain. Neurophysiologicalstudies have suggested that the prefrontal cortex plays a criticalrole in working memory,13-16 although other brain regions,notably the parietal cortex, also play an important role.17,18 Positron emission tomography (PET) and functional magneticresonance imaging (fMRI) studies have

investigated the neuralsubstrates of visuospatial working memory and its components,and most studies have shown significant prefrontal cortex aswell as parietal cortex involvement.19-23

Although there are a few behavioral and functional neuroimagingstudies involving subjects with fragile X syndrome,24-26 we are aware of no studies that have specifically examined workingmemory in this population, even by using behavioral measures.In this study, we investigated the neural substrates of workingmemory in female subjects with fragile X syndrome. Given that subjects with fragile X syndrome show significant deficits invisuospatial cognition as well as in executive function, wehypothesized that they would show significant impairment inperformance on visuospatial 1-back and 2back working memorytasks. We also hypothesized that they would show significantdeficits in activation in brain regions known to be involvedin working memory-particularly, the inferior and middlefrontal gyri, the dorsolateral prefrontal cortex, and the parietalcortex. Whole-brain voxel-by-voxel analyses were utilized toinvestigate differences in areas outside the regions of interest.We then examined possible correlations among behavioral measures, brain activation, and FMRP expression, as well as between IQand behavioral measures.