Journal of Autism and Developmental Disorders

, Volume 48, Issue 5, pp 1467–1482 | Cite as

Medial Frontal Lobe Neurochemistry in Autism Spectrum Disorder is Marked by Reduced N-Acetylaspartate and Unchanged Gamma-Aminobutyric Acid and Glutamate + Glutamine Levels

  • Andreia Carvalho Pereira
  • Inês R. Violante
  • Susana Mouga
  • Guiomar Oliveira
  • Miguel Castelo-Branco
Original Paper


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.


Autism spectrum disorder N-acetylaspartate Gamma-aminobutyric acid Glutamate + glutamine Creatine Autism diagnostic interview—revised 



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, 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 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.

Compliance with Ethical Standards

Conflict of interest

The authors have declared that no competing interests exist.

Supplementary material

10803_2017_3406_MOESM1_ESM.docx (185 kb)
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)
10803_2017_3406_MOESM2_ESM.docx (68 kb)
Supplementary material 2 (DOCX 67 KB)


  1. 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. Scholar
  2. 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.CrossRefGoogle Scholar
  3. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th edn.). Arlington: American Psychiatric Publishing.CrossRefGoogle Scholar
  4. 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. Scholar
  5. 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. Scholar
  6. 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. Scholar
  7. 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. Scholar
  8. 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. Scholar
  9. 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. Scholar
  10. 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. Scholar
  11. Benarroch, E. E. (2008). N-Acetylaspartate and N-acetylaspartylglutamate: Neurobiology and clinical significance. Neurology, 70(16), 1353–1357. Scholar
  12. 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. Scholar
  13. 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. Scholar
  14. Bozzi, Y., Provenzano, G., & Casarosa, S. (2017). Neurobiological bases of autism-epilepsy comorbidity: A focus on excitation/inhibition imbalance. European Journal of Neuroscience. Scholar
  15. 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. Scholar
  16. 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. Scholar
  17. Cecil, K. M. (2013). Proton magnetic resonance spectroscopy: technique for the neuroradiologist. Neuroimaging Clinics of North America, 23(3), 381–392. Scholar
  18. 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. Scholar
  19. Chugani, D. C. (2012). Neuroimaging and neurochemistry of autism. Pediatric Clinics of North America, 59(1), 63–73. Scholar
  20. 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. Scholar
  21. 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. Scholar
  22. Constantino, J. N., & Gruber, C. P. (2005). Social responsiveness scale (SRS). Los Angeles, CA: Western Psychological Services.Google Scholar
  23. 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. Scholar
  24. 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. Scholar
  25. 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. Scholar
  26. 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. Scholar
  27. 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. Scholar
  28. Ende, G. (2015). Proton magnetic resonance spectroscopy: Relevance of glutamate and GABA to neuropsychology. Neuropsychology Review, 25(3), 315–325. Scholar
  29. 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. Scholar
  30. 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. Scholar
  31. 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. Scholar
  32. 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. Scholar
  33. 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. Scholar
  34. Fombonne, E. (2003). Epidemiological surveys of autism and other pervasive developmental disorders: an update. Journal of autism and developmental disorders, 33(4), 365–382.
  35. Ford, T. C., & Crewther, D. P. (2016). A Comprehensive review of the 1H-MRS metabolite spectrum in autism spectrum disorder. Frontiers in Molecular Neuroscience. Scholar
  36. 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.
  37. 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. Scholar
  38. 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. Scholar
  39. Geschwind, D. H. (2009). Advances in autism. Annual Review of Medicine, 60, 367–380. Scholar
  40. 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. Scholar
  41. 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. Scholar
  42. 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. Scholar
  43. 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. Scholar
  44. 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. Scholar
  45. 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. Scholar
  46. 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. Scholar
  47. 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. Scholar
  48. 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. Scholar
  49. 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. Scholar
  50. 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. Scholar
  51. Lai, M.-C., Lombardo, M. V., & Baron-Cohen, S. (2014). Autism. The Lancet, 383(9920), 896–910. Scholar
  52. 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. Scholar
  53. Letzkus, J. J., Wolff, S. B. E., & Luthi, A. (2015). Disinhibition, a circuit mechanism for associative learning and memory. Neuron, 88(2), 264–276. Scholar
  54. 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. Scholar
  55. 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. Scholar
  56. 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. Scholar
  57. Lord, C., Rutter, M., DiLavore, P., & Risis, S. (1999). Autism diagnostic observation schedule (ADOS). Los Angeles: Western Psychological Services.Google Scholar
  58. 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. Scholar
  59. 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. Scholar
  60. Marín, O. (2012). Interneuron dysfunction in psychiatric disorders. Nature Reviews Neuroscience, 13(2), 107–120. Scholar
  61. Markram, H., Rinaldi, T., & Markram, K. (2007). The intense world syndrome–an alternative hypothesis for autism. Frontiers in Neuroscience, 1(1), 77–96. Scholar
  62. 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. Scholar
  63. 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.<266::AID-NBM530>3.0.CO;2-J PubMedCrossRefGoogle Scholar
  64. 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. Scholar
  65. 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. Scholar
  66. 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. Scholar
  67. 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. Scholar
  68. Morris, L. S., Baek, K., & Voon, V. (2016). Distinct cortico-striatal connections with subthalamic nucleus underlie facets of compulsivity. Cortex, 88, 143–150. Scholar
  69. 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. Scholar
  70. Murphy, D. (2002). Asperger syndrome: a proton magnetic resonance spectroscopy study of brain. Archives of General Psychiatry, 59(NOVEMBER), 885–891.
  71. 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. Scholar
  72. 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. Scholar
  73. 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. Scholar
  74. 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. Scholar
  75. 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. Scholar
  76. 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. Scholar
  77. 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. Scholar
  78. 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. Scholar
  79. 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.<73::AID-NBM448>3.0.CO;2-4 PubMedCrossRefGoogle Scholar
  80. Provencher, S. (1993). Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance in Medicine, 30(6), 672–679PubMedCrossRefGoogle Scholar
  81. Provencher, S. W. (2001). Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR in Biomedicine, 14(4), 260–264. Scholar
  82. 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. Scholar
  83. 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. Scholar
  84. 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. Scholar
  85. Robertson, C. E., Ratai, E.-M., & Kanwisher, N. (2015). Reduced GABAergic action in the autistic brain. Current Biology, 26(1), 80–85. Scholar
  86. 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. Scholar
  87. 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. Scholar
  88. 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. Scholar
  89. 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. Scholar
  90. Rutter, M., Bailey, A., & Lord, C. (2003). Social communication questionnaire. Los Angeles: Western Psychological Services.Google Scholar
  91. Rutter, M., Le Couteur, A., & Lord, C. (2003). The autism diagnostic interview-revised (ADI-R). Los Angeles, CA: Western Psychological Services.Google Scholar
  92. 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. Scholar
  93. 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. Scholar
  94. 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. Scholar
  95. 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. Scholar
  96. Spence, S. J., & Schneider, M. T. (2009). The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatric Research, 65(5), 5A–5A. Scholar
  97. 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. Scholar
  98. 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. Scholar
  99. Van Overwalle, F. (2009). Social cognition and the brain: A meta-analysis. Human Brain Mapping, 30(3), 829–858. Scholar
  100. 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. Scholar
  101. 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. Scholar
  102. 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. Scholar
  103. Wechsler, D. (2008). Manual for intelligence scale for adults. Portuguese version (M.R. Simões, A. M. Rocha, and C. Ferreira. Lisboa: Cegoc-Tea.Google Scholar
  104. Wechsler, D., Simoes, M. R., Rocha, A. M., & Ferreira, C. (2003). Wechsler Intelligence Scale for Children—Portuguese version. Lisboa: Cegoc-Tea.Google Scholar
  105. World Health Organization. (1992). ICD-10 classifications of mental and behavioural disorder clinical descriptions and diagnostic guidelines. Geneva: World Health Organization.Google Scholar
  106. Yasuhara, A. (2010). Correlation between EEG abnormalities and symptoms of autism spectrum disorder (ASD). Brain and Development, 32(10), 791–798. Scholar
  107. 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. Scholar
  108. Zikopoulos, B., & Barbas, H. (2013). Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Frontiers in Human Neuroscience, 7(September), 609. Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Institute for Biomedical Imaging and Life Sciences (CNC.IBILI), Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  2. 2.Sackler Institute for Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, Psychology and NeuroscienceKing’s College LondonLondonUK
  3. 3.The Computational, Cognitive and Clinical Neuroimaging Laboratory, Department of MedicineImperial College LondonLondonUK
  4. 4.Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança, Pediatric HospitalCentro Hospitalar e Universitário de CoimbraCoimbraPortugal
  5. 5.Centro de Investigação e Formação ClínicaHospital Pediátrico – Centro Hospitalar e Universitário de CoimbraCoimbraPortugal
  6. 6.University Clinic of Pediatrics, Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  7. 7.Institute of Nuclear Sciences Applied to Health (ICNAS), CiBIT, Brain Imaging Network of PortugalUniversity of CoimbraCoimbraPortugal

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