Dorsolateral Prefrontal Cortex Metabolic Profiles in Autism Spectrum Disorder Correlate Atypically with Nonverbal IQ and Typically with Attention Switching

Background The neurometabolic profile of associated with autism spectrum disorder (ASD) has been reported to be abnormal by some studies showing region specific metabolite levels in ASD, while others report no group differences. The neurometabolic profile of the left dorsolateral prefrontal cortex (DLPFC) is of particular interest due to the DLPFC relevance to cognitive and executive function, and to ASD. Method We used 1H-MRS to investigate neurometabolic profiles in the DLPFC of ASD and sex/IQ-matched typically developing (TD) children (ages 9-13). We focused on levels of Glutamate and Glutamine (Glx) due to many reported Glx abnormalities ASD, and of Choline (Cho) because of its relationship to intelligence quotient (IQ) and to attentional re-orienting difficulties. Results While no significant group differences were observed in absolute concentrations, metabolite levels were correlated with the behavioral phenotype of ASD children. In the ASD group but not the TD group, nonverbal IQ (NVIQ) was negatively associated with Cho (r=-0.59, p=0.026) and positively associated with Glx/Cr (r=0.66, p=0.011). Furthermore, attentional-switching scores in the ASD group correlated negatively with Cho (r=-0.69, p=0.009), and positively with Glx/Cr for both the ASD (r=0.73, p=0.004) and TD (r=0.54, p=0.040) groups. Conclusions Cho and Glx/Cr have different neurometabolic roles in modulating NVIQ in ASD compared to TD children, while their role in attentional switching seems preserved in ASD. Elucidating the apparently divergent role of neurometabolites in ASD in the absence of significant group differences in absolute levels is an important step towards understanding and mapping the neural correlates of ASD. These results are also relevant in the context of the significant cognitive function heterogeneity associated with the ASD phenotype, as they suggest possible underlying neural mechanisms that do not overlap which those expected from typical development. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the following: The National Institutes of Health (R01NS048455, MH); the Nancy Lurie Marks Foundation (MH); MIT-MGH Strategic Partnership grant from the Executive Committee on Research (ECOR) at Massachusetts General Hospital (EMR); the National Institute of Child Health and Development (R01HD073254, TK); the National Institute of Mental Health (R01MH117998, TK) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Massachusetts General Hospital gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors