Modulation of Inhibition Processing by Serotonin in Autism: An fMRI Study with Acute Tryptophan Depletion

Background:

A characteristic of Autism (ASD) is stereotyped and repetitive behaviors, symptoms that may be related to deficits in executive functions (EF); particularly inhibitory control of motor-response and interference inhibition. Research reports that inhibition tasks are mediated by the neurotransmitter serotonin (5-HT) and the 5-HT system is abnormal in ASD. Compared to controls, males with ASD showed increased brain activation when performing Go/No-Go task (GNG) of motor-inhibition and “Simon” task of cognitive-interference inhibition. Reduction of 5-HT by Acute Trypthophan Depletion (ATD) has shown a modulation of inhibition processing brain activation in healthy adults.  However, no one has examined this question in ASD.

Objectives:  

To study the modulatory role of 5-HT on stereotyped and repetitive  and obsessional behaviors, our objective was to compare the role of the 5-HT system on the neuroprocessing of two inhibitory tasks in people with ASD and controls using ATD and functional Magnetic Resonance Imaging (fMRI).

Methods:  

We scanned 14 high –functioning adult males (age 37(16-57); FSIQ IQ 115) with an ICD-10 diagnosis of ASD (confirmed using the ADI) and 14 gender, age and IQ matched control subjects. Subjects were tested on two separate occasions using a double-blind, placebo-controlled, crossover designed experiment.  An amino acid drink mixture was consumed on the both test dates after fasting from the previous day. The placebo or sham drink contained tryptophan, the precursor of 5-HT in the brain while the ATD drink did not contain tryptophan leading to the lowering of brain 5-HT. Then 4.5 hours post amino acid drink, subjects were scanned in a 1.5 Tesla GE Signa MRI machine measuring Blood Oxygenation Level Dependent (BOLD) signal while performing the GNG and SIMON inhibition tasks.  A 2 drink (SHAM,ATD) X 2 group (control, asperger) factorial repeated measures ANOVA of the BOLD signal was undertaken to determine brain regions where there was an interaction of 5-HT status and group. 

Results:  

Both groups showed a 70% blood tryptophan reduction after consumption of the ATD drink.  There were no differences in the performance of the task in either group, however, people with ASD showed significantly different brain activation patterns than controls in the 5-HT modulated experiments for both inhibition tasks. For the Go/No Go task, the interactions were found in the left-sided hippocampus, putamen and middle and inferior frontal gyri and right-sided temporal and occipital gyri while the Simon task, the interactions were found in bilateral caudate, temporal and parietal lobe, left-sided inferior frontal gyrus and right-sided insula. The interactions were an indication of a pattern of ‘opposite effects’ where ATD decreased the BOLD signal response for the controls and enhanced the BOLD signal response for ASDs in brain regions involved in inhibition.

Conclusions:  

Attenuation of 5-HT levels in the brain by ATD leads to opposite effects on the neuroprocessing of inhibition tasks in controls and males with ASD.  These results suggest that 5-HT dysfunction in ASD may be implicated in their altered brain activity during inhibition tasks and these differences in inhibitory control may contribute to the stereotyped and repetitive behaviors found in ASD.