Modulation of Simon Interference Inhibition Processing By Serotonin in Autism: A Pharmacologic Functional MRI Study with Acute Tryptophan Depletion
Stereotyped and repetitive behaviours constitute one domain of the classical triad of symptoms characterizing Autism Spectrum Disorder (ASD). Neurocognitive theories suggest that these symptoms may be related to deficits of interference-inhibitory control. In typically developing brain, inhibitory control tasks are mediated by the serotonergic (5-HT) system; e.g. reducing 5-HT by Acute Trypthophan Depletion (ATD) has been shown to modulate brain activation in the neurocognitive networks underlying inhibition processing in healthy controls (Rubia 2005). Individuals with ASD, however, show (i) atypical brain activation when performing tasks requiring cognitive interference inhibition (Schmitz 2006), and (ii) abnormalities in the 5-HT system (Zafierio 2009). However, direct evidence linking atypical 5-HT system to impaired inhibitory control in ASD remains is missing.
Here, we therefore examined the role of the 5-HT system in the neuroprocessing of interference-inhibition in people with ASD and neurotypical controls using pharmacologic functional Magnetic Resonance Imaging (pfMRI) involving ATD. We firstly established differences in the neurocognitive networks underlying interference-inhibition between individuals with ASD and controls. Secondly, we investigated whether modulation of the 5-HT neurotransmitter system by ATD differentially affected brain activity and task performance in the ASD and control groups.
14 adult males (age 37(16-57); FSIQ IQ 115) with an ADI-R confirmed diagnosis of ASD, and 14 matched controls were scanned on two separate occasions using a double-blind randomized, cross-over design on a 1.5T MRI scanner at the IoPPN, London. On one visit, a placebo (SHAM) amino acid drink was consumed. During the other visit, a Tryptophan depleted amino acid drink was consumed. At both occasions, fMRI scanning was performed using the EF Simon cognitive-interference inhibition task (ref). Order or active vs sham drink was randomized. Blood Oxygenation Level Dependent (BOLD) signal data were analyzed with the non-parametric image analysis software XBAM (www.brainmap.co.uk). To investigate the differential effect of tryptophan depletion on Simon inhibition processing, we performed 2 Group (Control, ASD) X 2 tryptophan status (SHAM, ATD) factorial designed ANOVA interactions.
There was a > 70% blood tryptophan reduction after consumption of the depletion drink in both groups. There were no differences in the performance of the task in either group. However, relative to controls, people with ASD showed an atypical pattern of brain activation. We found significant interactions between SHAM/ATD conditions and diagnostic groups in right medial frontal and left superior temporal gyri. In these regions, the interactions were an indication of a pattern of ‘normalization”, where ATD decreased the BOLD signal for the controls and enhancing the signal response for individuals with ASD.
Attenuation of 5-HT levels in the brain of individuals with ASD by ATD leads to ‘normalization’ of the neural networks involved in inhibition tasks relative to controls. These results suggest that 5-HT dysfunction in ASD may partially explain altered brain activity during inhibition tasks relative to healthy controls. If correct, this implies that the reducing brain 5-HT may be a novel theraputic approach in some individuals for autistic symptoms underpinned by abnormal inhibitory control.