Abstract
The nature of neurochemical changes in autism spectrum disorder (ASD) remains controversial. We compared medial prefrontal cortex (mPFC) neurochemistry of twenty high-functioning children and adolescents with ASD without associated comorbidities and fourteen controls. We observed reduced total N-acetylaspartate (tNAA) and total creatine, increased Glx/tNAA but unchanged glutamate + glutamine (Glx) and unchanged absolute or relative gamma-aminobutyric acid (GABA+) in the ASD group. Importantly, both smaller absolute and relative GABA+ levels were associated with worse communication skills and developmental delay scores assessed by the autism diagnostic interview—revised (ADI-R). We conclude that tNAA is reduced in the mPFC in ASD and that glutamatergic metabolism may be altered due to unbalanced Glx/tNAA. Moreover, GABA+ is related to autistic symptoms assessed by the ADI-R.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ajram, L. A., Horder, J., Mendez, M. A., Galanopoulos, A., Brennan, L. P., Wichers, R. H., et al. (2017). Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder. Translational Psychiatry, 7(5), e1137. https://doi.org/10.1038/tp.2017.104.
Alger, J. R. (2011). Quantitative proton magnetic resonance spectroscopy and spectroscopic imaging of the brain a didactic review. Topics in Magnetic Resonance Imaging: TMRI, 21(2), 115–128.
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th edn.). Arlington: American Psychiatric Publishing.
Arnold Anteraper, S., Triantafyllou, C., Sawyer, A. T., Hofmann, S. G., Gabrieli, J. D. & Whitfield-Gabrieli, S. (2014). Hyper-connectivity of subcortical resting-state networks in social anxiety disorder. Brain Connectivity, 4(2), 81–90. https://doi.org/10.1089/brain.2013.0180.
Aoki, Y., Abe, O., Yahata, N., Kuwabara, H., Natsubori, T., Iwashiro, N., et al. (2012). Absence of age-related prefrontal NAA change in adults with autism spectrum disorders. Translational Psychiatry, 2(10), e178. https://doi.org/10.1038/tp.2012.108.
Aoki, Y., Kasai, K., & Yamasue, H. (2012). Age-related change in brain metabolite abnormalities in autism: A meta-analysis of proton magnetic resonance spectroscopy studies. Translational Psychiatry, 2(1), e69. https://doi.org/10.1038/tp.2011.65.
Apps, M. A. J., Rushworth, M. F. S., & Chang, S. W. C. (2016). The anterior cingulate gyrus and social cognition: Tracking the motivation of others. Neuron, 90(4), 692–707. https://doi.org/10.1016/j.neuron.2016.04.018.
Badre, D., & D’Esposito, M. (2007). Functional magnetic resonance imaging evidence for a hierarchical organization of the prefrontal cortex. Journal of Cognitive Neuroscience, 19, 2082–2099. https://doi.org/10.1162/jocn.2007.19.12.2082.
Bartha, R. (2007). Effect of signal-to-noise ratio and spectral linewidth on metabolite quantification at 4 T. NMR in Biomedicine, 20(5), 512–521. https://doi.org/10.1002/nbm.1122.
Bejjani, A., O’Neill, J., Kim, J. A., Frew, A. J., Yee, V. W., Ly, R., et al. (2012). Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by1H MRS and 1H MRSI. PLoS ONE, 7(7), e38786. https://doi.org/10.1371/journal.pone.0038786.
Benarroch, E. E. (2008). N-Acetylaspartate and N-acetylaspartylglutamate: Neurobiology and clinical significance. Neurology, 70(16), 1353–1357. https://doi.org/10.1212/01.wnl.0000311267.63292.6c.
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, 57(1), 289–300. https://doi.org/10.2307/2346101.
Bollmann, S., Ghisleni, C., Poil, S.-S., Martin, E., Ball, J., Eich-Höchli, D., et al. (2015). Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder. Translational Psychiatry, 5, e589. https://doi.org/10.1038/tp.2015.79.
Bozzi, Y., Provenzano, G., & Casarosa, S. (2017). Neurobiological bases of autism-epilepsy comorbidity: A focus on excitation/inhibition imbalance. European Journal of Neuroscience. https://doi.org/10.1111/ejn.13595.
Brix, M. K., Ersland, L., Hugdahl, K., Grüner, R., Posserud, M.-B., Hammar, Å, et al. (2015). Brain MR spectroscopy in autism spectrum disorder—the GABA excitatory/inhibitory imbalance theory revisited. Frontiers in Human Neuroscience, 9(June), 1–12. https://doi.org/10.3389/fnhum.2015.00365.
Brunsdon, V. Ea, & Happé, F. (2014). Exploring the “fractionation” of autism at the cognitive level. Autism: The International Journal of Research and Practice, 18(1), 17–30. https://doi.org/10.1177/1362361313499456.
Cecil, K. M. (2013). Proton magnetic resonance spectroscopy: technique for the neuroradiologist. Neuroimaging Clinics of North America, 23(3), 381–392. https://doi.org/10.1016/j.nic.2012.10.003.
Chowdhury, F. A., O’Gorman, R. L., Nashef, L., Elwes, R. D., Edden, R. A., Murdoch, J. B., et al. (2015). Investigation of glutamine and GABA levels in patients with idiopathic generalized epilepsy using MEGAPRESS. Journal of Magnetic Resonance Imaging, 41(3), 694–699. https://doi.org/10.1002/jmri.24611.
Chugani, D. C. (2012). Neuroimaging and neurochemistry of autism. Pediatric Clinics of North America, 59(1), 63–73. https://doi.org/10.1016/j.pcl.2011.10.002.
Cleve, M., Gussew, A., & Reichenbach, J. R. (2015). In vivo detection of acute pain-induced changes of GABA + and Glx in the human brain by using functional 1H MEGA-PRESS MR spectroscopy. NeuroImage, 105, 67–75. https://doi.org/10.1016/j.neuroimage.2014.10.042.
Cochran, D. M., Sikoglu, E. M., Hodge, S. M., Edden, R. a. E., Foley, A., Kennedy, D. N., et al. (2015). Relationship among glutamine, γ-aminobutyric acid, and social cognition in autism spectrum disorders. Journal of Child and Adolescent Psychopharmacology, 25(4), 150428120459000. https://doi.org/10.1089/cap.2014.0112.
Constantino, J. N., & Gruber, C. P. (2005). Social responsiveness scale (SRS). Los Angeles, CA: Western Psychological Services.
Daly, E., Ecker, C., Hallahan, B., Deeley, Q., Craig, M., Murphy, C., et al. (2014). Response inhibition and serotonin in autism: A functional MRI study using acute tryptophan depletion. Brain, 137(9), 2600–2610. https://doi.org/10.1093/brain/awu178.
DeVito, T. J., Drost, D. J., Neufeld, R. W. J., Rajakumar, N., Pavlosky, W., Williamson, P., & Nicolson, R. (2007). Evidence for cortical dysfunction in autism: A proton magnetic resonance spectroscopic imaging study. Biological Psychiatry, 61(4), 465–473. https://doi.org/10.1016/j.biopsych.2006.07.022.
Drenthen, G. S., Barendse, E. M., Aldenkamp, A. P., van Veenendaal, T. M., Puts, N. A. J., Edden, R. A. E., et al. (2016). Altered neurotransmitter metabolism in adolescents with high-functioning autism. Psychiatry Research Neuroimaging, 256, 44–49. https://doi.org/10.1016/j.pscychresns.2016.09.007.
Edden, R. A. E., & Barker, P. B. (2007). Spatial effects in the detection of γ-aminobutyric acid: Improved sensitivity at high fields using inner volume saturation. Magnetic Resonance in Medicine, 58(6), 1276–1282. https://doi.org/10.1002/mrm.21383.
Edden, R. A. E., Pomper, M. G., & Barker, P. B. (2007). In vivo differentiation of N-acetyl aspartyl glutamate from N-acetyl aspartate at 3 T. Magnetic Resonance in Medicine, 57(6), 977–982. https://doi.org/10.1002/mrm.21234.
Ende, G. (2015). Proton magnetic resonance spectroscopy: Relevance of glutamate and GABA to neuropsychology. Neuropsychology Review, 25(3), 315–325. https://doi.org/10.1007/s11065-015-9295-8.
Fatemi, S. H., Halt, A. R., Stary, J. M., Kanodia, R., Schulz, S. C., & Realmuto, G. R. (2002). Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biological Psychiatry, 52(8), 805–810. https://doi.org/10.1016/S0006-3223(02)01430-0.
Fatemi, S. H., Reutiman, T. J., Folsom, T. D., Rooney, R. J., Patel, D. H., & Thuras, P. D. (2010). mRNA and protein levels for GABAAalpha4, alpha5, beta1 and GABABR1 receptors are altered in brains from subjects with autism. Journal of Autism and Developmental Disorders, 40(6), 743–750. https://doi.org/10.1007/s10803-009-0924-z.
Fatemi, S. H., Reutiman, T. J., Folsom, T. D., & Thuras, P. D. (2009). GABA(A) receptor downregulation in brains of subjects with autism. Journal of Autism and Developmental Disorders, 39(2), 223–230. https://doi.org/10.1007/s10803-008-0646-7.
Faul, F., Erdfelder, E., Buchner, A., & Lang, A.-G. (2009). Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behavior Research Methods, 41(4), 1149–1160. https://doi.org/10.3758/BRM.41.4.1149.
Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39(2), 175–191. https://doi.org/10.3758/BF03193146.
Fombonne, E. (2003). Epidemiological surveys of autism and other pervasive developmental disorders: an update. Journal of autism and developmental disorders, 33(4), 365–382. http://www.ncbi.nlm.nih.gov/pubmed/12959416.
Ford, T. C., & Crewther, D. P. (2016). A Comprehensive review of the 1H-MRS metabolite spectrum in autism spectrum disorder. Frontiers in Molecular Neuroscience. https://doi.org/10.3389/fnmol.2016.00014.
Fujii, E., Mori, K., Miyazaki, M., Hashimoto, T., Harada, M., & Kagami, S. (2010). Function of the frontal lobe in autistic individuals: a proton magnetic resonance spectroscopic study. The journal of medical investigation: JMI, 57(1–2), 35–44. http://www.ncbi.nlm.nih.gov/pubmed/20299741.
Gaetz, W., Bloy, L., Wang, D. J., Port, R. G., Blaskey, L., Levy, S. E., & Roberts, T. P. L. (2014). GABA estimation in the brains of children on the autism spectrum: Measurement precision and regional cortical variation. NeuroImage, 86, 1–9. https://doi.org/10.1016/j.neuroimage.2013.05.068.
Gasparovic, C., Song, T., Devier, D., Bockholt, H. J., Caprihan, A., Mullins, P. G., et al. (2006). Use of tissue water as a concentration reference for proton spectroscopic imaging. Magnetic Resonance in Medicine, 55(6), 1219–1226. https://doi.org/10.1002/mrm.20901.
Geschwind, D. H. (2009). Advances in autism. Annual Review of Medicine, 60, 367–380. https://doi.org/10.1146/annurev.med.60.053107.121225.
Goji, A., Ito, H., Mori, K., Harada, M., Hisaoka, S., Toda, Y., et al. (2017). Assessment of anterior cingulate cortex (ACC) and left cerebellar metabolism in asperger’s syndrome with proton magnetic resonance spectroscopy (MRS). Plos ONE, 12(1), e0169288. https://doi.org/10.1371/journal.pone.0169288.
Harada, M., Taki, M. M., Nose, A., Kubo, H., Mori, K., Nishitani, H., & Matsuda, T. (2011). Non-invasive evaluation of the GABAergic/glutamatergic system in autistic patients observed by MEGA-editing proton MR spectroscopy using a clinical 3 T instrument. Journal of Autism and Developmental Disorders, 41(4), 447–454. https://doi.org/10.1007/s10803-010-1065-0.
Harris, A. D., Puts, N. A. J., & Edden, R. A. E. (2015). Tissue correction for GABA-edited MRS: Considerations of voxel composition, tissue segmentation, and tissue relaxations. Journal of Magnetic Resonance Imaging, 42(5), 1431–1440. https://doi.org/10.1002/jmri.24903.
Hashimoto, T., Sasaki, M., Sugai, K., Hanaoka, S., Fukumizu, M., Kato, T., et al. (2001). Paroxysmal discharges on EEG in young autistic patients are frequent in frontal regions. Journal of Medical Investigation, 48(3–4), 175–180. http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L33545846%5Cnhttp://sfx.library.uu.nl/utrecht?sid=EMBASE&issn=13431420&id=doi:&atitle=Paroxysmal+discharges+on+EEG+in+young+autistic+patients+are+frequent+in+frontal+regions.&stitle=.
Hassan, T. H., Abdelrahman, H. M., Abdel Fattah, N. R., El-Masry, N. M., Hashim, H. M., El-Gerby, K. M., & Abdel Fattah, N. R. (2013). Blood and brain glutamate levels in children with autistic disorder. Research in Autism Spectrum Disorders, 7(4), 541–548. https://doi.org/10.1016/j.rasd.2012.12.005.
Hodge, S. M., Makris, N., Kennedy, D. N., Caviness, V. S., Howard, J., McGrath, L., et al. (2010). Cerebellum, language, and cognition in autism and specific language impairment. Journal of Autism and Developmental Disorders, 40(3), 300–316. https://doi.org/10.1007/s10803-009-0872-7.
Horder, J., Lavender, T., Mendez, M., O’Gorman, R., Daly, E., Craig, M. C., et al. (2013). Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [1H]MRS study. Translational Psychiatry, 3(April), e279. https://doi.org/10.1038/tp.2013.53.
Ipser, J. C., Syal, S., Bentley, J., Adnams, C. M., Steyn, B., & Stein, D. J. (2012). 1H-MRS in autism spectrum disorders: A systematic meta-analysis. Metabolic Brain Disease, 27(3), 275–287. https://doi.org/10.1007/s11011-012-9293-y.
Ito, H., Mori, K., Harada, M., Hisaoka, S., Toda, Y., Mori, T., et al. (2017). A proton magnetic resonance spectroscopic study in autism spectrum disorder using a 3-tesla clinical magnetic resonance imaging (MRI) System: The anterior cingulate cortex and the left cerebellum. Journal of Child Neurology, 32(8), 88307381770298. https://doi.org/10.1177/0883073817702981.
Joshi, G., Biederman, J., Wozniak, J., Goldin, R. L., Crowley, D., Furtak, S., et al. (2013). Magnetic resonance spectroscopy study of the glutamatergic system in adolescent males with high-functioning autistic disorder: A pilot study at 4T. European Archives of Psychiatry and Clinical Neuroscience, 263(5), 379–384. https://doi.org/10.1007/s00406-012-0369-9.
Kubas, B., Kułak, W., Sobaniec, W., Tarasow, E., Lebkowska, U., & Walecki, J. (2012). Metabolite alterations in autistic children: a 1H MR spectroscopy study. Advances in Medical Sciences, 57(1), 152–156. https://doi.org/10.2478/v10039-012-0014-x.
Lai, M.-C., Lombardo, M. V., & Baron-Cohen, S. (2014). Autism. The Lancet, 383(9920), 896–910. https://doi.org/10.1016/S0140-6736(13)61539-1.
Landim, R. C. G., Edden, R. A. E., Foerster, B., Li, L. M., Covolan, R. J. M., & Castellano, G. (2015). Investigation of NAA and NAAG dynamics underlying visual stimulation using MEGA-PRESS in a functional MRS experiment. Magnetic Resonance Imaging, 34(3), 239–245. https://doi.org/10.1016/j.mri.2015.10.038.
Letzkus, J. J., Wolff, S. B. E., & Luthi, A. (2015). Disinhibition, a circuit mechanism for associative learning and memory. Neuron, 88(2), 264–276. https://doi.org/10.1016/j.neuron.2015.09.024.
Lever, A. G., & Geurts, H. M. (2016). Psychiatric Co-occurring symptoms and disorders in young, middle-aged, and older adults with autism spectrum disorder. Journal of Autism and Developmental Disorders. https://doi.org/10.1007/s10803-016-2722-8.
Li, C. T., Lu, C. F., Lin, H. C., Huang, Y. Z., Juan, C. H., Su, T. P., et al. (2017). Cortical inhibitory and excitatory function in drug-naive generalized anxiety disorder. Brain Stimulation, 10(3), 604–608. https://doi.org/10.1016/j.brs.2016.12.007.
Long, Z., Dyke, J. P., Ma, R., Huang, C. C., Louis, E. D., & Dydak, U. (2015). Reproducibility and effect of tissue composition on cerebellar γ-aminobutyric acid (GABA) MRS in an elderly population. NMR in Biomedicine, 28(10), 1315–1323. https://doi.org/10.1002/nbm.3381.
Lord, C., Rutter, M., DiLavore, P., & Risis, S. (1999). Autism diagnostic observation schedule (ADOS). Los Angeles: Western Psychological Services.
Maddock, R. J., Casazza, G. A., Fernandez, D. H., & Maddock, M. I. (2016). Acute modulation of cortical glutamate and GABA content by physical activity. Journal of Neuroscience, 36(8), 2449–2457. https://doi.org/10.1523/JNEUROSCI.3455-15.2016.
Maltezos, S., Horder, J., Coghlan, S., Skirrow, C., O’Gorman, R., Lavender, T. J., et al. (2014). Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study. Translational Psychiatry, 4(3), e373. https://doi.org/10.1038/tp.2014.11.
Marín, O. (2012). Interneuron dysfunction in psychiatric disorders. Nature Reviews Neuroscience, 13(2), 107–120. https://doi.org/10.1038/nrn3155.
Markram, H., Rinaldi, T., & Markram, K. (2007). The intense world syndrome–an alternative hypothesis for autism. Frontiers in Neuroscience, 1(1), 77–96. https://doi.org/10.3389/neuro.01.1.1.006.2007.
Mendez, M. A., Horder, J., Myers, J., Coghlan, S., Stokes, P., Erritzoe, D., et al. (2013). The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [11C]Ro15–4513 positron emission tomography study. Neuropharmacology, 68, 195–201. https://doi.org/10.1016/j.neuropharm.2012.04.008.
Mescher, M., Merkle, H., Kirsch, J., Garwood, M., & Gruetter, R. (1998). Simultaneous in vivo spectral editing and water suppression. NMR in Biomedicine, 11(6), 266–272. https://doi.org/10.1002/(SICI)1099-1492(199810)11:6<266::AID-NBM530>3.0.CO;2-J
Mlynrik, V., Gruber, S., & Moser, E. (2001). Proton T1 and T2 relaxation times of human brain metabolites at 3 T. NMR in Biomedicine, 14(5), 325–331. https://doi.org/10.1002/nbm.713.
Moffett, J. R., Arun, P., Ariyannur, P. S., & Namboodiri, A. M. A. (2013). N-Acetylaspartate reductions in brain injury: Impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation. Frontiers in Neuroenergetics, 5(DEC), 1–19. https://doi.org/10.3389/fnene.2013.00011.
Mori, K., Toda, Y., Ito, H., Mori, T., Goji, A., Fujii, E., et al. (2013). A proton magnetic resonance spectroscopic study in autism spectrum disorders: Amygdala and orbito-frontal cortex. Brain and Development, 35(2), 139–145. https://doi.org/10.1016/j.braindev.2012.09.016.
Mori, T., Mori, K., Fujii, E., Toda, Y., Miyazaki, M., Harada, M., et al. (2012). Evaluation of the GABAergic nervous system in autistic brain: 123I-iomazenil SPECT study. Brain and Development, 34(8), 648–654. https://doi.org/10.1016/j.braindev.2011.10.007.
Morris, L. S., Baek, K., & Voon, V. (2016). Distinct cortico-striatal connections with subthalamic nucleus underlie facets of compulsivity. Cortex, 88, 143–150. https://doi.org/10.1016/j.cortex.2016.12.018.
Mouga, S., Café, C., Almeida, J., Marques, C., Duque, F., & Oliveira, G. (2016). Intellectual profiles in the autism spectrum and other neurodevelopmental disorders. Journal of Autism and Developmental Disorders, 46(9), 2940–2955. https://doi.org/10.1007/s10803-016-2838-x.
Murphy, D. (2002). Asperger syndrome: a proton magnetic resonance spectroscopy study of brain. Archives of General Psychiatry, 59(NOVEMBER), 885–891. http://archpsyc.jamanetwork.com/article.aspx?articleid=206824.
Naaijen, J., Lythgoe, D. J., Amiri, H., Buitelaar, J. K., & Glennon, J. C. (2015). Fronto-striatal glutamatergic compounds in compulsive and impulsive syndromes: A review of magnetic resonance spectroscopy studies. Neuroscience and Biobehavioral Reviews, 52, 74–88. https://doi.org/10.1016/j.neubiorev.2015.02.009.
Neale, J. H., Bzdega, T., & Wroblewska, B. (2000). N-acetylaspartylglutamate: The most abundant peptide neurotransmitter in the mammalian central nervous system. Journal of Neurochemistry, 75(2), 443–452. https://doi.org/10.1046/j.1471-4159.2000.0750443.x.
O’Gorman, R. L., Michels, L., Edden, R. A., Murdoch, J. B., & Martin, E. (2011). In vivo detection of GABA and glutamate with MEGA-PRESS: Reproducibility and gender effects. Journal of Magnetic Resonance Imaging, 33(5), 1262–1267. https://doi.org/10.1002/jmri.22520.
Oblak, a, Gibbs, T. T., & Blatt, G. J. (2009). Decreased GABAA receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism. Autism Research : Official Journal of the International Society for Autism Research, 2(4), 205–219. https://doi.org/10.1002/aur.88.
Oblak, A. L., Gibbs, T. T., & Blatt, G. J. (2010). Decreased GABAB receptors in the cingulate cortex and fusiform gyrus in Autism. Journal of Neurochemistry, 114(5), 1414–1423. https://doi.org/10.1111/j.1471-4159.2010.06858.x.
Oliveira, G., Ataide, A., Marques, C., Miguel, T. S., Coutinho, A. M., Mota-Vieira, L., et al. (2007). Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical characterization, and medical conditions. Developmental Medicine & Child Neurology, 49(10), 726–733. https://doi.org/10.1111/j.1469-8749.2007.00726.x.
Patel, T., Blyth, J. C., Griffiths, G., Kelly, D., & Talcott, J. B. (2014). Moderate relationships between NAA and cognitive ability in healthy adults: implications for cognitive spectroscopy. Frontiers in Human Neuroscience, 8(February), 39. https://doi.org/10.3389/fnhum.2014.00039.
Port, R. G., Gaetz, W., Bloy, L., Wang, D. J., Blaskey, L., Kuschner, E. S., et al. (2016). Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: Evidence for an altered maturational trajectory in ASD. Autism Research. https://doi.org/10.1002/aur.1686.
Pouwels, P. J. W., & Frahm, J. (1997). Differential distribution of NAA and NAAG in human brain as determined by quantitative localized proton MRS. NMR in Biomedicine, 10(2), 73–78. https://doi.org/10.1002/(SICI)1099-1492(199704)10:2<73::AID-NBM448>3.0.CO;2-4
Provencher, S. (1993). Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance in Medicine, 30(6), 672–679
Provencher, S. W. (2001). Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR in Biomedicine, 14(4), 260–264. https://doi.org/10.1002/nbm.698.
Puts, N. A. J., Wodka, E. L., Harris, A. D., Crocetti, D., Tommerdahl, M., Mostofsky, S. H., & Edden, R. A. E. (2016). Reduced GABA and altered somatosensory function in children with autism spectrum disorder. Autism Research, 10, 608–619. https://doi.org/10.1002/aur.1691.
Rae, C. D. (2014). A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochemical Research, 39(1), 1–36. https://doi.org/10.1007/s11064-013-1199-5.
Ribeiro, M. J., Violante, I. R., Bernardino, I., Edden, R. A. E., & Castelo-Branco, M. (2015). Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1. Cortex, 64, 194–208. https://doi.org/10.1016/j.cortex.2014.10.019.
Robertson, C. E., Ratai, E.-M., & Kanwisher, N. (2015). Reduced GABAergic action in the autistic brain. Current Biology, 26(1), 80–85. https://doi.org/10.1016/j.cub.2015.11.019.
Rojas, D. C., Becker, K. M., & Wilson, L. B. (2014a). Magnetic resonance spectroscopy studies of glutamate and GABA in autism: Implications for excitation-inhibition imbalance theory. Current Developmental Disorders Reports, 2, 46–57. https://doi.org/10.1007/s40474-014-0032-4.
Rojas, D. C., Singel, D., Steinmetz, S., Hepburn, S., & Brown, M. S. (2014b). Decreased left perisylvian GABA concentration in children with autism and unaffected siblings. NeuroImage, 86, 28–34. https://doi.org/10.1016/j.neuroimage.2013.01.045.
Rowland, L. M., Krause, B. W., Wijtenburg, S., McMahon, R. P., Chiappelli, J., Nugent, K. L., et al. (2015). Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study. Molecular Psychiatry. https://doi.org/10.1038/mp.2015.34.
Rubenstein, J. L. R., & Merzenich, M. M. (2003). Model of autism : increased ratio of excitation / inhibition in key neural systems. Genes, Brain and Behavior, 2(5), 255–267. https://doi.org/10.1046/j.1601-183X.2003.00037.x.
Rutter, M., Bailey, A., & Lord, C. (2003). Social communication questionnaire. Los Angeles: Western Psychological Services.
Rutter, M., Le Couteur, A., & Lord, C. (2003). The autism diagnostic interview-revised (ADI-R). Los Angeles, CA: Western Psychological Services.
Scholl, J., Kolling, N., Nelissen, N., Stagg, C. J., Harmer, C. J., & Rushworth, M. F. (2017). Excitation and inhibition in anterior cingulate predict use of past experiences. eLife, 6, 1–15. https://doi.org/10.7554/eLife.20365.
Schür, R. R., Draisma, L. W. R., Wijnen, J. P., Boks, M. P., Koevoets, M. G. J. C., Joëls, M., et al. (2016). Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of 1 H-MRS studies. Human Brain Mapping, 37(April), 3337–3352. https://doi.org/10.1002/hbm.23244.
Shungu, D. C., Mao, X., Gonzales, R., Soones, T. N., Dyke, J. P., van der Veen, J. W., & Kegeles, L. S. (2016). Brain gamma-aminobutyric acid (GABA) detection in vivo with the J-editing 1H MRS technique: a comprehensive methodological evaluation of sensitivity enhancement, macromolecule contamination and test-retest reliability. NMR in Biomedicine, 29(7), 932–942. https://doi.org/10.1002/nbm.3539.
Solleveld, M., Schrantee, A., Puts, N., Reneman, L., & Lucassen, P. (2017). Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients. NeuroImage: Clinical. https://doi.org/10.1016/j.nicl.2017.06.003.
Spence, S. J., & Schneider, M. T. (2009). The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatric Research, 65(5), 5A–5A. https://doi.org/10.1203/01.pdr.0000352115.41382.65.
Takahashi, H., Katayama, K., Sohya, K., Miyamoto, H., Prasad, T., Matsumoto, Y., et al. (2012). Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction. Nature Neuroscience, 15(3), 389–398. https://doi.org/10.1038/nn.3040.
Tebartz Van Elst, L., Maier, S., Fangmeier, T., Endres, D., Mueller, G., Nickel, K., et al. (2014). Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: evidence in support of the excitatory/inhibitory imbalance hypothesis. Molecular Psychiatry, 19(12), 1314–132562. https://doi.org/10.1038/mp.2014.62.
Van Overwalle, F. (2009). Social cognition and the brain: A meta-analysis. Human Brain Mapping, 30(3), 829–858. https://doi.org/10.1002/hbm.20547.
Varghese, M., Keshav, N., Jacot-Descombes, S., Warda, T., Wicinski, B., Dickstein, D. L., et al. (2017). Autism spectrum disorder: neuropathology and animal models. Acta Neuropathologica, 134(4), 537–566. https://doi.org/10.1007/s00401-017-1736-4.
Violante, I. R., Patricio, M., Bernardino, I., Rebola, J., Abrunhosa, A. J., Ferreira, N., & Castelo-Branco, M. (2016). GABA deficiency in NF1. Neurology, 87(9), 897–904. https://doi.org/10.1212/WNL.0000000000003044.
Violante, I. R., Ribeiro, M. J., Edden, R. A. E., Guimares, P., Bernardino, I., Rebola, J., et al. (2013). GABA deficit in the visual cortex of patients with neurofibromatosis type 1: Genotype-phenotype correlations and functional impact. Brain, 136(3), 918–925. https://doi.org/10.1093/brain/aws368.
Wechsler, D. (2008). Manual for intelligence scale for adults. Portuguese version (M.R. Simões, A. M. Rocha, and C. Ferreira. Lisboa: Cegoc-Tea.
Wechsler, D., Simoes, M. R., Rocha, A. M., & Ferreira, C. (2003). Wechsler Intelligence Scale for Children—Portuguese version. Lisboa: Cegoc-Tea.
World Health Organization. (1992). ICD-10 classifications of mental and behavioural disorder clinical descriptions and diagnostic guidelines. Geneva: World Health Organization.
Yasuhara, A. (2010). Correlation between EEG abnormalities and symptoms of autism spectrum disorder (ASD). Brain and Development, 32(10), 791–798. https://doi.org/10.1016/j.braindev.2010.08.010.
Zaroff, C. M., & Uhm, S. Y. (2012). Prevalence of autism spectrum disorders and influence of country of measurement and ethnicity. Social Psychiatry and Psychiatric Epidemiology, 47(3), 395–398. https://doi.org/10.1007/s00127-011-0350-3.
Zikopoulos, B., & Barbas, H. (2013). Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Frontiers in Human Neuroscience, 7(September), 609. https://doi.org/10.3389/fnhum.2013.00609.
Acknowledgments
The authors thank all participants and their families for their willingness to participate in this study. The authors thank Dr. Inês Bernardino for support in the neuropsychological evaluation of control participants and Dr. João Castelhano for creating Matlab scripts for MEGA-PRESS combined spectra visualization. The authors are also grateful to the staff of the Institute of Nuclear Sciences Applied to Health (ICNAS, http://www.uc.pt/en/icnas) for their technical assistance with the magnetic resonance scanning, particularly to Mr. Carlos Ferreira, Mr. João Marques and Ms. Sónia Afonso. This research was supported by the Portuguese Foundation for Science and Technology grants: BIGDATIMAGE, CENTRO-01-0145-FEDER-000016 financed by Centro 2020 FEDER, COMPETE, FLAD Life Sciences Ed 2 2016, COMPETE, POCI-01-0145-FEDER-007440, FCT. UID/NEU/04539/2013–2020, PAC – MEDPERSYST POCI-01-0145-FEDER-016428; IRV is funded by is funded by the Wellcome Trust (103045/Z/13/Z), SM is funded by Portuguese Foundation for Science and Technology (individual scholarship: SFRH/BD/102779/2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Contributions
Conceived and designed the study: ACP IRV MC-B and GO. Acquired data: ACP and SM. Analysed the data: ACP and IRV. Interpreted the data ACP and MC-B. Wrote original draft: ACP and MC-B. All authors reviewed and edited the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors have declared that no competing interests exist.
Electronic supplementary material
Below is the link to the electronic supplementary material.
10803_2017_3406_MOESM1_ESM.docx
Figure 1S. MEGA-PRESS mean fit (red line) and standard deviation (shaded red) of the difference spectra for each group. Abbreviations: Glx, glutamate+glutamine; GABA+, gamma-aminobutyric acid + lipids and macromolecules; tNAA, N-acetylaspartate + N-acetylaspartylglutamate; MM. macromolecules; ppm, parts per million. (DOCX 184 KB)
Rights and permissions
About this article
Cite this article
Carvalho Pereira, A., Violante, I.R., Mouga, S. et al. Medial Frontal Lobe Neurochemistry in Autism Spectrum Disorder is Marked by Reduced N-Acetylaspartate and Unchanged Gamma-Aminobutyric Acid and Glutamate + Glutamine Levels. J Autism Dev Disord 48, 1467–1482 (2018). https://doi.org/10.1007/s10803-017-3406-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10803-017-3406-8