Frontostriatal deficits in fragile X syndrome: relation to FMR1 gene expression.
Fragile X syndrome (fraX) is the most common known cause of inherited developmental disability. fraX is associated with a CGG expansion in the FMR1 gene on the long arm of the X chromosome. Behavioral deficits, including problems with impulse control and distractibility, are common in fraX. We used functional brain imaging with a Go/NoGo task to examine the neural substrates of response inhibition in females with fraX (ages 10-22) and age- and gender-matched typically developing subjects. Although subjects with fraX had significantly lower IQ scores, as a group their performance on the Go/NoGo task was equivalent to that of the typically developing group. However, females with fraX showed abnormal activation patterns in several cortical and subcortical regions, with significantly reduced activation in the supplementary motor area, anterior cingulate and midcingulate cortex, basal ganglia, and hippocampus. An important finding of our study is that neural responses in the right ventrolateral prefrontal cortex (PFC) and the left and right striatum were correlated with the level of FMR1 gene expression. Our findings support the hypothesis that frontostriatal regions typically associated with response inhibition are dysfunctional in females with fraX. In addition to task-related activation deficits, reduced levels of "deactivation" were observed in the ventromedial PFC, and, furthermore, these reductions were correlated with the level of FMR1 gene expression. The ventromedial PFC is a key node in a "default mode" network that monitors mental and physiological states; we suggest that self-monitoring processes may be aberrant in fraX.
Department of Psychiatry and Behavioral Sciences, Program in Neuroscience, and Stanford Brain Research Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. menon@stanford.edu
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Menon
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Leroux
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White
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Reiss
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D003342:Corpus Striatum / Q000503:physiopathology*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D015870:Gene Expression; D006801:Humans; D008279:Magnetic Resonance Imaging; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000503:physiopathology*; D016601:RNA-Binding Proteins
D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human