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 common known heritable cause of neurodevelopmental disability. This study examined the neural substrates of working memory in female subjects with fragile X syndrome. Possible correlations among behavioral measures, brain activation, and the FMR1 gene product (FMRP expression), as well as between IQ and behavioral measures, were investigated.


METHODS
Functional magnetic resonance imaging was used to examine visuospatial working memory in 10 female subjects with fragile X syndrome and 15 typically developing female subjects (ages 10-23 years). Subjects performed standard 1-back and 2-back visuospatial working memory tasks. Brain activation was examined in four regions of the cortex known to play a critical role in visuospatial working memory. Correlations between behavioral, neuroimaging, 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 task. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, comparison subjects showed significantly increased brain activation between the 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. Significant correlations were found 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 the 1-back task. In subjects with fragile X syndrome, significant correlations were found during the 2-back task between FMRP expression and activation in the right inferior and bilateral middle frontal gyri and the bilateral supramarginal gyri.


CONCLUSIONS
Subjects with fragile X syndrome are unable to modulate activation in the prefrontal and parietal cortex in response to an increasing working memory load, and these deficits are related to a lower level of FMRP expression 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.
Kwon
H
H
Department of Psychiatry, Stanford University School of Medicine, CA 94305-5719, USA. hower.kwon@stanford.edu
Menon
V
V
Eliez
S
S
Warsofsky
I S
IS
White
C D
CD
Dyer-Friedman
J
J
Taylor
A K
AK
Glover
G H
GH
Reiss
A L
AL
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000033:anatomy & histology* / Q000378:metabolism / Q000502:physiology*; D001923:Brain Chemistry / Q000235:genetics; D002648:Child; D015897:Comorbidity; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D007839:Functional Laterality / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D007360:Intelligence / Q000145:classification; D016014:Linear Models; D008279:Magnetic Resonance Imaging / Q000706:statistics & numerical data; D008569:Memory Disorders / Q000175:diagnosis* / Q000453:epidemiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D011597:Psychomotor Performance / Q000502:physiology*; D016601:RNA-Binding Proteins; D013028:Space Perception / Q000502:physiology; D014796:Visual Perception / Q000502:physiology*; D014888:Wechsler Scales / Q000706:statistics & numerical data
D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human