Inviduals with ASD had significantly reduced levels of cerebral Glx and Ins when compared with HC. Specifically, Glx concentrations were significantly reduced in the right ACC. Ins concentrations were significantly reduced in the left TPJ. The finding of significantly lower Glx concentrations in the ASD sample is consistent with previous findings in children with widespread Glx reduction in most cerebral lobes and cerebellum (DeVito et al. 2007
). Our results complement the previous study and provide replication in an adult sample not taking psychotropic medications, with the application of a short TE.
The frontal cortex, the temporal cortex, and the basal ganglia develop heterochronically; changes in metabolite concentrations have been reported across different developmental ages (Horska et al. 2002
). Thus, by analyzing a sample of adults with ASD we have also provided information about the stability of differences in Glx concentration shown in previous studies conducted in childhood. Only one study analyzed Glx concentration in a similar population to the one recruited in this study (Page et al. 2006
), however, the analyses were limited to the amygdalohippocampal region and reported a significantly higher Glx concentration with 1.5 T 1
H-MRS (Schumann et al. 2009
It is important to note that the resonance group attributed to Glx includes contribution from glutamate/GABA and glutamine, and therefore a reduction in any or all of these compounds may be responsible for the reduction in Glx. However, previous studies have cautiously attributed Glx reduction to glutamate, as it constitutes the most abundant central neurotransmitter (DeVito et al. 2007
;Hardan et al. 2008
;Page et al. 2006
). Glutamate plays a critical role in neurodevelopmental processes such as neuronal migration, differentiation, and plasticity (Coyle et al. 2002
). Autism is associated with abnormal brain development (Nicolson and Szatmari 2003
) and this study provides further evidence of impaired glutamatergic transmission previously implicated in the pathophysiology of ASD (Carlsson 1998
;DeVito et al. 2007
;Page et al. 2006
;Polleux and Lauder 2004
Our analyses localized the reduction in Glx concentration in the right ACC. Decreased metabolism and smaller volume of the ACC have been reported in individuals with ASD (Haznedar et al. 1997
), and a quantitative meta-analysis of imaging studies in autism reported the ACC as the region with higher likelihood of hypoactivation (Di Martino et al. 2009
;Haznedar et al. 1997
). The imbalance between excitation and inhibition in the cortex of ASD may cause disruption of the synchrony of the ACC neurons that are thought to be necessary for executive control (Fan et al. 2005
;MacDonald, III et al. 2000
;Posner et al. 2007
). A preliminary hypothesis may involve a reduction of the prefrontal glutamate-stimulated release of dopamine from terminals of the ventral tegmental area or substantia nigra. These systems are considered to be important in the processes of movement, learning, reward, motivation (Wise 2008
), and error monitoring (Pourtois et al. 2009
), all functions subject to top-down control, which is impaired in ASD (Brian et al. 2003
;Hughes et al. 1994
;Shu et al. 2001
). Interestingly, a recent study reported enhancement in the regulation of dopamine release in the substantia nigra in an animal model of attention deficit/ hyperactivity disorder (Warton et al. 2009
), another disorder with deficits in attention and impaired executive control (Swanson 2003
). Future studies of connectivity may provide further insight into this hypothesis.
We also found a reduced concentration of Ins in the left TPJ. Myo-inositol is a metabolic compound located mostly in astrocytes. High Ins levels are thought to indicate cell growth and have also been directly associated with performance IQ scores in ASD (Gabis et al. 2008
). The difference in Ins concentrations in left TPJ was also the only model to demonstrate a statistical trend toward a main effect of IQ. TPJ has been associated with orienting function of attention (Fan and Posner 2004
), and also with phasic response and tonic maintenance of the alert state to a warning signal (Fan et al. 2005
). The TPJ has also been repeatedly implicated in mechanisms underlying empathy in healthy individuals (Jackson et al. 2006
), in autism (Williams et al. 2006
), and in other diseases as well (Benedetti et al. 2009
Contrary to previous findings in children (Friedman et al. 2003
;Levitt et al. 2003
), there were no significant differences in Cho. Given that Cho compounds are thought to be related to membrane turnover, differences in age-related cellular metabolisms may explain the incongruence with findings in childhood, although this may also be due to type II errors due to small sample size.
Several limitations are important to consider in interpreting these results. First, the small sample size and exclusion of patients with nonverbal IQ ≤ 80 limit generalization of the conclusions. Yet, the main effect of IQ as covariate on Glx concentrations was not significant and did not alter the significance of the model, suggesting that the results of this study are not solely due to the effect of IQ. Second, the MRS protocol employed in the present study did not allow for quantitative determination of glutamate concentration, which has been shown to appear well separated from glutamine at 3 T with an echo time of 80 ms (Schubert et al. 2004
). However, the TE employed was short, as is generally required to maximize signal yield by reducing the effects of scalar coupling on the Glx signal. Future studies employing spectral editing techniques to fit glutamate and glutamine spectra separately are needed to confirm these results and to determine if the changes in Glx are due to glutamine, glutamate, or both. Furthermore, future 1
H-MRS studies may employ editing techniques to examine the GABAergic concentrations in those regions to shed further light on the etiological hypothesis of ASD as imbalance of excitatory and inhibitory neurotransmission.
In conclusion, high-functioning adults with ASD had a significant reduction of Glx concentration in the ACC, suggesting abnormalities in neurotransmission involved in the executive control of attention previously implicated in ASD pathogenesis.
Furthermore, our results demonstrate a reduced concentration of Ins in the left TPJ, suggesting a role for a region previously implicated in orienting functions of attention. Future studies of the connectivity of the ACC and ventral tegmental area/substantia nigra may provide further insight to the role of glutamate in the executive control of attention.