Modulation of brain activation during executive functioning in autism with citalopram

Abstract

Adults with autism spectrum disorder (ASD) are frequently prescribed selective serotonin reuptake inhibitors (SSRIs). However, there is limited evidence to support this practice. Therefore, it is crucial to understand the impact of SSRIs on brain function abnormalities in ASD. It has been suggested that some core symptoms in ASD are underpinned by deficits in executive functioning (EF). Hence, we investigated the role of the SSRI citalopram on EF networks in 19 right-handed adult males with ASD and 19 controls who did not differ in gender, age, IQ or handedness. We performed pharmacological functional magnetic resonance imaging to compare brain activity during two EF tasks (of response inhibition and sustained attention) after an acute dose of 20 mg citalopram or placebo using a randomised, double-blind, crossover design. Under placebo condition, individuals with ASD had abnormal brain activation in response inhibition regions, including inferior frontal, precentral and postcentral cortices and cerebellum. During sustained attention, individuals with ASD had abnormal brain activation in middle temporal cortex and (pre)cuneus. After citalopram administration, abnormal brain activation in inferior frontal cortex was 'normalised' and most of the other brain functional differences were 'abolished'. Also, within ASD, the degree of responsivity in inferior frontal and postcentral cortices to SSRI challenge was related to plasma serotonin levels. These findings suggest that citalopram can 'normalise' atypical brain activation during EF in ASD. Future trials should investigate whether this shift in the biology of ASD is maintained after prolonged citalopram treatment, and if peripheral measures of serotonin predict treatment response.

Fig. 1

Brain activation map showing abnormally activated regions during response inhibition and sustained attention in ASD that were ‘normalised’ by citalopram; p < 0.02 at cluster level. Location of BOLD signal changes between groups. Red: TD < ASD; Blue: TD > ASD. Numeric label = z Talairach coordinate. Right hemisphere of brain is on the right side of the image. Abbreviations: BOLD, blood-oxygen-level dependent; TD, Typically Developed Controls; ASD, Individuals with Autism Spectrum Disorder

Fig. 2

Significant decrease (‘normalisation’) in brain activation during response inhibition in left inferior frontal cortex within ASD following citalopram administration. Abbreviations: SSQ, sum of squares (statistical measure of BOLD response); * = p < 0.05

Fig. 3

Interaction of drug status (placebo, citalopram) by group (TD, ASD) during response inhibition; p < 0.02 at cluster level. Location of BOLD signal for ANOVA interaction. Numeric label = z Talairach coordinate. Box plots: Mean BOLD signal extracted from each interaction cluster. Right hemisphere of brain is on the right side of the image. Abbreviations: SSQ, sum of squares fMRI statistic; BOLD, blood-oxygen-level dependent; TD, Typically Developed Controls; ASD, Individuals with Autism Spectrum Disorder