Skip to main content
SpringerLink
Log in

Non-Invasive Evaluation of the GABAergic/Glutamatergic System in Autistic Patients Observed by MEGA-Editing Proton MR Spectroscopy Using a Clinical 3 Tesla Instrument

  • Original Paper
  • Published:
Journal of Autism and Developmental Disorders Aims and scope Submit manuscript

Abstract

Amino acids related to neurotransmitters and the GABAergic/glutamatergic system were measured using a 3 T-MRI instrument in 12 patients with autism and 10 normal controls. All measurements were performed in the frontal lobe (FL) and lenticular nuclei (LN) using a conventional sequence for n-acetyl aspartate (NAA) and glutamate (Glu), and the MEGA-editing method for GABA. The GABA level and [GABA]/[NAA] ratio were significantly lower (p < 0.01) in the FL, but not the LN, in patients with autism compared to normal controls. The [GABA]/[Glu] ratio in the FL was also significantly lower (p < 0.05) in the patients than in the normal controls, thus suggesting a possible abnormality in the regulation between GABA and Glu.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Aasly, J., Silfvenius, H., Aas, T. C., Sonnewald, U., Olivecrona, M., Juul, R., et al. (1999). Proton magnetic resonance spectroscopy of brain biopsies from patients with intractable epilepsy. Epilepsy Research, 35, 211–217.

    Article  PubMed  Google Scholar 

  • Aldred, S., Moore, K. M., Fitzgerald, M., & Waring, R. H. (2003). Plasma amino acid levels in children with autism and their families. Journal of Autism and Developmental Disorders, 33, 449–454.

    Article  Google Scholar 

  • Baslow, M. H. (2003). N-acetylaspartate in the vertebrate brain: Metabolism and function. Neurochemical Research, 28, 941–953.

    Article  PubMed  Google Scholar 

  • Bauman, M., & Kemper, T. L. (1985). Histoanatomic observations of the brain in early infantile autism. Neurology, 35, 866–874.

    PubMed  Google Scholar 

  • Choi, C., Bhardwaj, P. P., Kalra, S., Casault, C. A., Yasmin, U. S., Allen, P. S., et al. (2007). Measurement of GABA and contaminants in gray and white matter in human brain in vivo. Magnetic Resonance in Medicine, 58, 27–33.

    Article  PubMed  Google Scholar 

  • Choi, I.-Y., Lee, S.-P., Merkle, H., & Shen, J. (2006). In vivo detection of gray and white matter differences in GABA concentration in the human brain. NeuroImage, 33, 85–93.

    Article  PubMed  Google Scholar 

  • Cook, E. H., Courchesne, R. Y., Cox, N. J., Lord, C., Gonen, D., Guter, S. J., et al. (1998). Linkage-disequilibrium mapping of autistic disorder, with 15q11–13 Markers. American Journal of Human Genetics, 62, 1077–1083.

    Article  PubMed  Google Scholar 

  • Cote, C. J., & Wilson, S. (2006). Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: An update. Pediatrics, 118, 2587–2602.

    Article  PubMed  Google Scholar 

  • Devito, T. J., Drost, D. J., Neufeld, R. W., Rajakumar, N., Pavlosky, W., Williamson, P., et al. (2007). Evidence for cortical dysfunction in autism: A proton magnetic resonance spectroscopic imaging study. Biological Psychiatry, 61, 465–473.

    Article  PubMed  Google Scholar 

  • Fatemi, S. H., Folsom, T. D., Reutiman, T. J., Thuras, P. D. (2008). Expression of GABAB receptors is altered in brains of subjects with autism. Cerebellum Nov 12 (Epub ahead of print).

  • 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, 805–810.

    Article  PubMed  Google Scholar 

  • Fatemi, S. H., Reutiman, T. J., Folsom, T. D., & Thuras, P. D. (2009). GABAA receptor downregulation in brains of subjects with autism. Journal of Autism and Developmental Disorders, 39, 223–230.

    Article  PubMed  Google Scholar 

  • Friedman, S. D., Shaw, D. W. W., Artru, A. A., Dawson, G., Petropoulos, H., & Dager, S. R. (2006). Gray and white matter brain chemistry in young children with autism. Archives of General Psychiatry, 63, 786–794.

    Article  PubMed  Google Scholar 

  • Friedman, S. D., Shaw, D. W., Artru, A. A., Richards, T. L., Gardner, J., Dawson, G., et al. (2003). Regional brain chemical alterations in young children with autism spectrum disorder. Neurology, 60, 100–107.

    PubMed  Google Scholar 

  • Guptill, J. T., Booker, A. B., Gibbs, T. T., Kemper, T. L., Bauman, M. L., & Blatt, G. J. (2007). [3H]-FLunitrazepam-labeled benzodiazepine binding sites in the hippocampal formation in autism: A multiple concentration autoradiographic study. Journal of Autism and Developmental Disorders, 37, 911–920.

    Article  PubMed  Google Scholar 

  • Harada, M., Kubo, H., Nose, A., Nishitani, H., Matsuda, T. (in press) Measurement of variation in the human cerebral GABA level by in vivo MEGA-editing proton MR spectroscopy using a clinical 3 Tesla instrument and its dependence on brain region and the female menstrual cycle. Hum Brain Mapp.

  • Harada, M., Miyoshi, H., Uno, M., Okada, T., Hisaoka, S., Hori, A., et al. (1999). Neuronal impairment of adult moyamoya disease detected by quantified proton MRS and comparison with cerebral perfusion by SPECT with Tc-99m HM-PAO: A trial of clinical quantification of metabolites. Journal of Magnetic Resonance Imaging, 10, 124–129.

    Article  PubMed  Google Scholar 

  • Hisaoka, S., Harada, M., Nishitani, H., & Mori, K. (2001). Regional magnetic resonance spectroscopy of the brain in autistic individuals. Neuroradiology, 43, 496–498.

    Article  PubMed  Google Scholar 

  • Jensen, J. E., de Frederick, B., & Renshaw, P. F. (2005). Gray and white matter GABA level difference in the human brain using two-dimensional J-resolved spectroscopic imaging. NMR Biomed, 18, 570–576.

    Article  PubMed  Google Scholar 

  • Lam, K. S. L., Aman, M. G., & Arnold, L. E. (2006). Neurochemical correlates of autistic disorder: A review of the literature. Research in Developmental Disabilities, 27, 254–289.

    Article  PubMed  Google Scholar 

  • Levitt, J. G., O’Neill, J., McCracken, J. T., Guthrie, D., Toga, A. W., & Alger, J. R. (2003). Proton magnetic resonance spectroscopic imaging in childhood autism. Biological Psychiatry, 54, 1355–1366.

    Article  PubMed  Google Scholar 

  • Lotspeich, L. J., & Ciaranello, R. D. (1993). The neurobiology and genetics of infantile autism. International Review of Neurobiology, 35, 87–129.

    Article  PubMed  Google Scholar 

  • Ma, D. Q., Whitehead, P. L., Menold, M. M., etMartin, E. R., Ashley-Koch, A. E., Mei, H., et al. (2005). Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet, 77, 377–388.

    Article  PubMed  Google Scholar 

  • Meshcer, M., Merkle, H., Kirsch, J., Garwood, M., & Gruetter, R. (1998). Simultaneous in vivo spectral editing and water suppression. NMR in Biomedicine, 11, 266–272.

    Article  Google Scholar 

  • Murphy, D. G., Critchley, H. D., Schmitz, N., MacAlonan, G., van Amelsvoort, T., Robertson, D., et al. (2002). Asperger syndrome: A proton magnetic resonance study of brain. Archives of General Psychiatry, 59, 885–891.

    Article  PubMed  Google Scholar 

  • Novotny, E. J., Jr., Hyder, F., Shevell, M., & Rothman, D. L. (1999). GABA changes with vigabatrin in the developing human brain. Epilepsia., 40, 462–466.

    Article  PubMed  Google Scholar 

  • Otsuka, H., Harada, M., Mori, K., Hisaoka, S., & Nishitani, H. (1999). Brain metabolites in the hippocampus-amygdala region and cerebellum in autism: An 1H-MR spectroscopy study. Neuroradiology, 41, 517–519.

    Article  PubMed  Google Scholar 

  • Oz, G., Terpstra, M., Tkac, I., Aia, P., Lowary, J., Tuite, P. J., et al. (2006). Proton MRS of the unilateral substantia nigra in the human brain at 4 Tesla: Detection of high GABA concentrations. Magnetic Resonance in Medicine, 55, 296–301.

    Article  PubMed  Google Scholar 

  • Page, L. A., Daly, E., Schmitz, N., Simmons, A., Toal, F., Deeley, Q., et al. (2006). In vivo 1H-magnetic resonance spectroscopy study of amygdale-hippocampal and parietal regions in autism. American Journal of Psychiatry, 163, 2189–2192.

    Article  PubMed  Google Scholar 

  • Petroff, O. A. C., Behar, K. L., Mattson, R. H., & Rothman, D. L. (1996). Human brain γ-aminobutyric acid levels and seizure control following initiation of vigabatrin therapy. Journal of Neurochemistry, 67, 2399–2404.

    Article  PubMed  Google Scholar 

  • Petroff, O. A. C., Ogino, T., & Alger, J. R. (1988). High-resolution proton magnetic resonance spectroscopy of rabbit brain: Regional metabolite levels and postmortem changes. Journal of Neurochemistry, 51, 163–171.

    Article  PubMed  Google Scholar 

  • Petroff, O. A. C., Rothman, D. L., Behar, K. L., & Mattson, R. H. (1995). Initial observations on effect of vigabatrin on in vivo 1H spectroscopic measurements of γ-aminobutyric acid, glutamate, and glutamine in human brain. Epilepsia, 36, 457–464.

    Article  PubMed  Google Scholar 

  • Pouwels, P. J. W., Brockmann, K., Kruse, B., Wilken, B., Wick, M., Hanefeld, F., et al. (1999). Regional age dependence of human brain metabolites from infancy to adulthood as detected by quantitative localized proton MRS. Pediatric Research, 46, 474–485.

    Article  PubMed  Google Scholar 

  • Provencher, S. E. (1993). Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance in Medicine, 30, 672–679.

    Article  PubMed  Google Scholar 

  • Samaco, R. C., Hogart, A., & Lasalle, J. M. (2004). Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Human Molecular Genetics, 14, 483–492.

    Article  PubMed  Google Scholar 

  • Shinohe, A., Hashimoto, K., Nakamura Tsujii, M., Iwata, Y., Tsuchiya, K. J., Sekine, Y., et al. (2006). Increase serum levels of glutamate in adult patients with autism. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 30, 1472–1477.

    Article  PubMed  Google Scholar 

  • Terpstra, M., Henry, P.-G., & Gruetter, R. (2003). Measurement of reduced glutathione (GSH) in human brain using LCModel analysis of difference-edited spectra. Magnetic Resonance in Medicine, 50, 19–23.

    Article  PubMed  Google Scholar 

  • Terpstra, M., Ugurbil, K., & Gruetter, R. (2002). Direct in vivo measurement of human cerebral GABA concentration using MEGA-editing at 7 Tesla. Magnetic Resonance in Medicine, 47, 1009–1012.

    Article  PubMed  Google Scholar 

  • Weber, O. M., Verhagen, A., Duc, C. O., Meier, D., Leenders, K. L., & Boesiger, P. (1999). Effects of vigabatrin intake on brain GABA activity as monitored by spectrally edited magnetic resonance spectroscopy and positron emission tomography. Magnetic Resonance Imaging, 17, 417–425.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research (B) No. 19390321 form the Japan Society for the Promotion of Science (JSPS) and a Grant from the Japanese Society of Neuroradiology.

Author information

Authors and Affiliations

  1. Department of Medical Imaging, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-Cho, Tokushima, 770-8509, Japan

    Masafumi Harada & Hitoshi Kubo

  2. Department of Radiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503, Japan

    Masako M. Taki, Ayumi Nose & Hiromu Nishitani

  3. Department of Pediatrics, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-Cho, Tokushima, 770-8509, Japan

    Kenji Mori

  4. GE-Healthcare Japan, Ltd., 4-7-127 Asahigaoka, Hino, Tokyo, 191-8503, Japan

    Tsuyoshi Matsuda

Authors
  1. Masafumi Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masako M. Taki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ayumi Nose
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hitoshi Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenji Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiromu Nishitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tsuyoshi Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masafumi Harada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harada, M., Taki, M.M., Nose, A. et al. Non-Invasive Evaluation of the GABAergic/Glutamatergic System in Autistic Patients Observed by MEGA-Editing Proton MR Spectroscopy Using a Clinical 3 Tesla Instrument. J Autism Dev Disord 41, 447–454 (2011). https://doi.org/10.1007/s10803-010-1065-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10803-010-1065-0

Keywords

Search

Navigation