Acute Fluoxetine Leads to Increased Prefrontal Activation in Children with Autism Spectrum Disorder During Tasks of Executive Function

Background: Patients with Autism Spectrum Disorders (ASD) have shown abnormal performance and activation in frontal, striatal and parietal regions during tasks of working memory, inhibition and cognitive flexibility. Genetic and biochemical studies have shown that serotonin (5-HT) dysregulation may play a pivotal role in cognition and behaviour in ASD. Furthermore, there is some evidence that Selective Serotonin Reuptake Inhibitors (SSRIs) such as Fluoxetine improve ASD behaviours. In healthy adults, serotonin manipulation has been shown to affect neural networks of inhibition and attention functions. However, nothing is known of the effects of SSRIs on brain function in people with ASD.

Objectives: In this study we therefore aimed to investigate the effect of a single acute clinical dose of Fluoxetine on brain function in children with ASD during disorder-relevant tasks of working memory, inhibition and reversal learning. We hypothesised that the single dose would enhance activation in task-relevant prefrontal and temporo-parietal brain regions.  

Methods: Twelve medication-naïve right handed boys with the clinical DSM-IV diagnosis of ASD, aged 10-17, IQ < 70 with no co-morbidities were recruited from local clinics. Boys were assessed using the Autism Diagnostic Interview – Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) to confirm diagnosis. Each subject underwent two functional magnetic resonance imaging scans (fMRI) (four weeks apart), either under placebo (peppermint water), or a single clinical dose of Fluoxetine (titrated to weight), in a double-blind, cross-over, placebo-controlled design performing 3 executive function tasks: a working memory (WM) (NBack) task, a Stop task measuring motor response inhibition and a Reversal Learning task, measuring cognitive flexibility. The effects of Fluoxetine on performance and brain activation in patients were tested using repeated-measures ANOVAs. The analysis package of XBAM was used for brain image analyses.  

Results: No significant performance changes were observed under Fluoxetine. In the WM task Fluoxetine relative to placebo increased rostro-medial and dorsolateral prefrontal (DLPFC) but decreased precuneus activation, which was at a trend-level anti-correlated with DLPFC activation. During successful reversal learning trials, Fluoxetine relative to placebo increased rostro-medial prefrontal while decreasing bilateral striatum activation.  During successful inhibition in the Stop task, Fluoxetine relative to placebo increased activation in right inferior frontal cortex (IFC).   

Conclusions: These preliminary findings show that Fluoxetine upregulates activation in task specific, serotonergically innervated prefrontal brain regions, i.e.in right IFC for inhibition, rostromedial PFC for reversal learning; and DLPFC for WM, which are typically abnormally activated in ASD populations. Furthermore, during WM this was also associated with deactivation of default mode regions.  Our ongoing work compares the modulatory effect of Fluoxetine in larger samples of ASD to controls and patients with Attention Deficit Hyperactivity Disorder.