Decreased brain serotonin transporter binding in ASD; intranasal oxytocin administration: effects on computerized social discrimination task and eye-tracking


Decreased Brain Serotonin Transporter Binding in ASD [Nakamura et al., 2010]

Serotonin has been implicated in ASD since the initial report of increased serotonin in the blood of children with ASD in 1961 [Schain & Freedman, 1961]. After decades of investigation, the mechanism of the elevation in blood serotonin is not fully understood, although either reduced serotonin 5-HT2 binding or increased serotonin transporter function were found in hyperserotonemic subjects in one study [Cook et al., 1993]. It is important to recognize that the peripheral serotonin increase applies only to a minority of subjects with ASD. Because of challenges in measuring central serotonin function in ASD, there have been few previous studies of serotonin in the brains of individuals with ASD. To date, in vivo study of serotonin in brain has been limited to studies in which radioactively tagged molecules (radioligands) that bind to serotonin proteins (serotonin receptors or transporters) are administered intravenously and taken into the brain where they bind to 5-HT receptors (e.g. 5-HT2) or the 5-HT transporter. SPECT or PET methods are then used to measure binding of the radioligands to the brain serotonin-related proteins.

The authors used the compound [11C]-trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methyltrio)phenyl]pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652) as a radioligand to bind to serotonin transporter molecules. The radioligand 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C] WIN-35,428) was used to study dopamine transporter binding. An increase in WIN-35,428 binding was found in the orbital frontal cortex. However, since it was P 0.02 voxel-corrected (in the region), but not a multiple region-corrected finding, it may have occurred by chance. Therefore, the reported inverse correlation with serotonin transporter binding in the ASD subjects in this region may have occurred by chance as well. Therefore, the remainder of the review will focus on serotonin transporter binding.

Compared to 20 age- and IQ-matched control men, the 20 adult men (age range 18–26 years; IQ mean 99.3 and standard deviation 18.1) with ASD had reduced serotonin transporter binding throughout the brain. The authors spent considerable time in the manuscript discussing regional differences both in magnitude of the reduction and in correlation with ASD symptoms. However, given the global nature of the reduction and the effects of imprecision of measurement of regions of interest with PET, the regional differences in correlations with symptoms were less convincing.

It would have been useful to have measured blood serotonin and related measures (e.g. platelet serotonin transporter binding and function). It would also have been useful to have genotyped controls and individuals with ASD both for common variants regulating gene expression and rare amino acid variants altering protein function of the serotonin transporter. Without those measures, the paradox of a minority of subjects with increased 5-HT transporter function peripherally cannot be reconciled with the current study's finding of reduced central 5-HT transporter function of the whole group. One possibility is that a minority of subjects with ASD have increased serotonin transporter function but that the larger group may have a reduction in serotonin transporter function, but that will require further investigation.

This focused study provides information about the overall finding of reduced serotonin transporter binding in ASD in a group of subjects that as a whole had average IQ scores. Further study will be necessary to understand the relationship of this overall finding to specific aspects of phenotype in ASD.

▪ Intranasal Oxytocin Administration: Effects on Computerized Social Discrimination Task and Eye-Tracking [Andari et al., 2010]

Oxytocin (OT) is a neuropeptide hormone with a range of functions, including social effects. As reviewed in this manuscript, previous work has demonstrated reduced plasma oxytocin levels in ASD and association with the oxytocin receptor gene in several studies of ASD. Intravenously administered OT has been demonstrated to reduce repetitive behavior and to improve comprehension of affective information in speech.

In the manuscript under review, the authors conducted two related experiments. In the first set of experiments, 11 adult men and 2 adult women with DSM-IV-TR diagnosed Asperger's disorder (N=10) or autistic disorder (N=3) were studied. All subjects were reported to have above average general cognitive functioning. They were compared to 13 group age-matched and sex-matched controls. The social task used was a computer simulation of a sharing task in which balls were passed to one of the three figures representing “players.” The experimenters established three profiles of computer-participants. The profiles were based on how frequently the non-subject “participant” would return the ball to the subject. There was a neutral profile (sending the ball back 1/3 of the time), positive profile (sending the ball more often back to the subject than the other 2 “participants”), and a negative profile (sending the ball to the subject less often than chance). After placebo, the subjects with ASD did not return the balls more to the positive profile participant than the other two, but controls showed a significant difference in returning the “balls” back to the positive compared to the negative “participant.” After intranasal OT, the subjects with ASD not only showed the response pattern of the control subjects, but also provided ratings of preference and trust that indicated they better “understood” the differential responding of the computer-simulated participants. There was an economic basis to the task in this experiment, and so the findings were replicated in a smaller independent set of subjects without this incentive and similar results were obtained.

In the second set of experiments, the same 13 original subjects with ASD looked at faces while identifying gender of faces and while determining eye gaze. There was reduced eye gaze towards faces compared to controls in both conditions. More time was spent looking at faces and the eye region of the face after oxytocin in the ASD subjects, but this was still reduced relative to controls.

The sample size in this manuscript was small. In addition, there was no evidence of a clinically meaningful improvement, given that sensitive laboratory measures with no direct measurement of social function were employed. The effects of intrasal OT are fleeting and there is concern about the effects of exogenous chronic administration of an endogenous neuroactive hormone, with examples of concern being related to downregulation of OT receptors. The authors appropriately emphasized that their study does not have immediate clinical applications. The study does provide further evidence of the role of OT in social function in ASD. Given the rapidly increasing basic knowledge of OT in social function, this study is one of a series of interesting studies to track in ASD research.