Autism and EEG phase reset: deficient GABA mediated inhibition in thalamo-cortical circuits.

The purpose of this study was to explore the relationship between electroencephalogram (EEG) phase reset in autism spectrum disorder (ASD) subjects as compared to age matched control subjects. The EEG was recorded from 19 scalp locations from 54 autistic subjects and 241 control subjects ranging in age from 2.6 years to 11 years. Complex demodulation was used to compute instantaneous phase differences between all pairs of electrodes and the 1st and 2nd derivatives were used to measure phase reset by phase shift duration and phase lock duration. In both short (6 cm) and long (21-24 cm) inter-electrode distances phase shift duration in ASD subjects was significantly shorter in all frequency bands but especially in the alpha-1 frequency band (8-10 Hz) (p < .0001). Phase lock duration was significantly longer in the alpha-2 frequency band (10-12 Hz) in ASD subjects (p < .0001). An anatomical gradient was present with the occipital-parietal regions the most significant. The findings in this study support the hypothesis that neural resource recruitment occurs in the lower frequency bands and especially the alpha-1 frequency band while neural resource allocation occurs in the alpha-2 frequency band. The results are consistent with a general GABA inhibitory neurotransmitter deficiency resulting in reduced number and/or strength of thalamo-cortical connections in autistic subjects.

Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15.

Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p<0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16(+)/CD56(+) cells. When the NK cytotoxic activity was expressed based on activity/100 CD16(+)/CD56(+) cells, several patients who had displayed NK cell activity below 15 LU exhibited normal NK cell activity. Overall, after this correction factor, 45% of the children with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. Finally, we cultured lymphocytes of patients with low or high NK cell activity/cell with or without glutathione, IL-2 and IL-15. The induction of NK cell activity by IL-2, IL-15 and glutathione was more pronounced in a subgroup with very low NK cell activity. We conclude that that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible.

Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.

BACKGROUND: Autism is a complex neurodevelopmental disorder that usually presents in early childhood and that is thought to be influenced by genetic and environmental factors. Although abnormal metabolism of methionine and homocysteine has been associated with other neurologic diseases, these pathways have not been evaluated in persons with autism. OBJECTIVE: The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism. DESIGN: Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of the autistic children. RESULTS: Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. CONCLUSIONS: An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.