Brain circuitry, behavior, and cognition: A randomized placebo-controlled trial of donepezil in fragile X syndrome

Abstract

Background: Fragile X syndrome, the most common inherited cause for intellectual disability, is associated with alterations in cholinergic among other neurotransmitter systems. This study investigated the effects of donepezil hydrochloride, a cholinesterase inhibitor that has potential to correct aberrant cholinergic signaling.

Method: Forty-two individuals with fragile X syndrome (mean age=19.61 years) were randomized to receive 2.5-10.0 mg of donepezil (n=20, seven females) or placebo (n=22, eight females) per day. One individual in the active group withdrew at week 7. Outcomes included the contingency naming test, the aberrant behavior checklist, and behavior and brain activation patterns during a functional magnetic resonance imaging gaze discrimination task.

Results: There were no significant differences between active and placebo groups on cognitive (contingency naming task) or behavioral (total score or subscales of the aberrant behavior checklist) outcomes. At baseline, the active and placebo groups did not differ in functional magnetic resonance imaging activation patterns during the gaze task. After 12 weeks of treatment the active group displayed reduced activation in response to the averted vs direct gaze contrast, relative to the placebo group, in the left superior frontal gyrus.

Conclusions: Reduced functional brain activation for the active group may represent less arousal in response to direct eye gaze, relative to the placebo group. Change in functional magnetic resonance imaging activation patterns may serve as a more sensitive metric and predictor of response to treatment when compared to cognitive and behavioral assessments. Our results suggest that donepezil may have an impact on brain functioning, but longer term follow-up and concomitant behavioral intervention may be required to demonstrate improvement in cognition and behavior.

Keywords: Clinical trial; autism spectrum disorder; fragile X syndrome; functional magnetic resonance imaging; neuroimaging.

Figure 1.

Participant flow diagram.

Figure 2.

Contingency naming test scores pre and post treatment. CNT = contingency naming test, scores represent the number of correct items per minute. Solid lines indicate active group scores and dashed lines indicate placebo group scores. Error bars represent standard error.

Figure 3.

Aberrant behavior checklist scores pre and post treatment. ABC = aberrant behavior checklist. Solid lines indicate active group scores and dashed lines indicate placebo group scores. Error bars represent standard error.

Figure 4.

fMRI results Top panel: Group level performance for judging eye gaze during fMRI task. Squares represent mean values and error bars indicate standard error. RT = reaction time. Bottom panel: Group difference in brain activation after treatment with donepezil. Note that comparison of group activation differences pre-treatment revealed no significant group difference (p<0.05, FWE). Brain activation patterns at follow up shown in A) sagittal, B) coronal and C) axial views. In B and C left side of images = left side of brain. Yellow color indicates regions for which individuals in the placebo group demonstrated greater activation relative to the active group (T values for direct>averted gaze stimuli, height threshold = 0.001, corrected for multiple comparison, FWE < 0.05). Cross hair corresponds to peak at x=−18, y=36, z=40. Sub cluster peaks were found at x=−22, y=24, z=34 and x=−10, y=34, z=36.