Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study

Molecular Psychiatry volume 21, pages 198–204 (2016)Cite this article

Subjects

Abstract

Gamma-butyric acid (GABA) dysfunction has been implicated in the pathophysiology of schizophrenia and its cognitive deficits. Proton magnetic resonance spectroscopy (MRS) was used to test the hypothesis that older participants with schizophrenia have lower anterior cingulate GABA levels compared with older control participants. One-hundred forty-five participants completed this study. For detection of GABA, spectra were acquired from the medial frontal/anterior cingulate cortex using a macromolecule-suppressed MEGA-PRESS sequence. Patients were evaluated for psychopathology and all participants completed neuropsychological tests of working memory, processing speed and functional capacity. GABA levels were significantly lower in the older participants with schizophrenia (n=31) compared with the older control (n=37) group (P=0.003) but not between the younger control (n=40) and schizophrenia (n=29) groups (P=0.994). Age strongly predicted GABA levels in the schizophrenia group accounting for 42% of the variance, but the effect of age was less in the control group accounting for 5.7% of the variance. GABA levels were specifically related to working memory but not processing speed performance, functional capacity, or positive or negative symptom severity. This is the largest MRS study of GABA in schizophrenia and the first to examine GABA without macromolecule contamination, a potentially significant issue in previous studies. GABA levels more rapidly declined with advancing age in the schizophrenia compared with the control group. Interventions targeted at halting the decline or increasing GABA levels may improve functional outcomes and quality of life as patients with schizophrenia age.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Curtis DR, Duggan AW, Felix D, Johnston GA . GABA bicuculline and central inhibition. Nature 1970; 226: 1222–1224.

    Article  CAS  Google Scholar 

  2. Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–324.

    Article  CAS  Google Scholar 

  3. Benes FM, Berretta S . GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25: 1–27.

    Article  CAS  Google Scholar 

  4. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 1995; 52: 258–266.

    Article  CAS  Google Scholar 

  5. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000; 57: 1061–1069.

    Article  CAS  Google Scholar 

  6. Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 2003; 23: 6315–6326.

    Article  CAS  Google Scholar 

  7. Gonzalez-Burgos G, Hashimoto T, Lewis DA . Alterations of cortical GABA neurons and network oscillations in schizophrenia. Curr Psychiatry Rep 2010; 12: 335–344.

    Article  Google Scholar 

  8. Vincent SL, Sorensen I, Benes FM . Localization and high-resolution imaging of cortical neurotransmitter compartments using confocal laser scanning microscopy: GABA and glutamate interactions in rat cortex. BioTechniques 1991; 11: 628–634.

    CAS  PubMed  Google Scholar 

  9. Volk DW, Lewis DA . GABA targets for the treatment of cognitive dysfunction in schizophrenia. Curr Neuropharmacol 2005; 3: 45–62.

    Article  CAS  Google Scholar 

  10. Costa E, Guidotti A, Veldic M . Should allosteric positive modulators of GABA(A) receptors be tested in the treatment of schizophrenia? Schizophr Res 2005; 73: 367–368.

    Article  Google Scholar 

  11. Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HM, Volk DW et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2008; 13: 147–161.

    Article  CAS  Google Scholar 

  12. Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R . Simultaneous in vivo spectral editing and water suppression. NMR Biomed 1998; 11: 266–272.

    Article  CAS  Google Scholar 

  13. Aufhaus E, Weber-Fahr W, Sack M, Tunc-Skarka N, Oberthuer G, Hoerst M et al. Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: a MEGA-PRESS study with symmetric editing pulse frequencies for macromolecule suppression. Magn Reson Med 2013; 69: 317–320.

    Article  CAS  Google Scholar 

  14. Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X et al. Elevated prefrontal cortex gamma-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2012; 69: 449–459.

    Article  CAS  Google Scholar 

  15. Ongur D, Prescot AP, McCarthy J, Cohen BM, Renshaw PF . Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biol Psychiatry 2010; 68: 667–670.

    PubMed  PubMed Central  Google Scholar 

  16. Goto N, Yoshimura R, Kakeda S, Moriya J, Hori H, Hayashi K et al. No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage first-episode schizophrenia. Prog Neuro-psychopharmacol Biol Psychiatry 2010; 34: 1480–1483.

    Article  CAS  Google Scholar 

  17. Kelemen O, Kiss I, Benedek G, Keri S . Perceptual and cognitive effects of antipsychotics in first-episode schizophrenia: the potential impact of GABA concentration in the visual cortex. Prog Neuro-psychopharmacol Biol Psychiatry 2013; 47: 13–19.

    Article  CAS  Google Scholar 

  18. Rowland LM, Kontson K, West J, Edden RA, Zhu H, Wijtenburg SA et al. In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. Schizophr Bull 2013; 39: 1096–1104.

    Article  Google Scholar 

  19. Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD et al. GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 2010; 30: 3777–3781.

    Article  CAS  Google Scholar 

  20. de la Fuente-Sandoval C, Leon-Ortiz P, Azcarraga M, Favila R, Stephano S, Graff-Guerrero A . Striatal glutamate and the conversion to psychosis: a prospective 1H-MRS imaging study. Int J Neuropsychopharmacol 2013; 16: 471–475.

    Article  CAS  Google Scholar 

  21. de la Fuente-Sandoval C, Leon-Ortiz P, Azcarraga M, Stephano S, Favila R, Diaz-Galvis L et al. Glutamate levels in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis: a longitudinal proton magnetic resonance spectroscopy study. JAMA Psychiatry 2013; 70: 1057–1066.

    Article  CAS  Google Scholar 

  22. de la Fuente-Sandoval C, Leon-Ortiz P, Favila R, Stephano S, Mamo D, Ramirez-Bermudez J et al. Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis. Neuropsychopharmacology 2011; 36: 1781–1791.

    Article  CAS  Google Scholar 

  23. Marsman A, van den Heuvel MP, Klomp DW, Kahn RS, Luijten PR, Hulshoff Pol HE . Glutamate in schizophrenia: a focused review and meta-analysis of (1)H-MRS studies. Schizophr Bull 2013; 39: 120–129.

    Article  Google Scholar 

  24. Henry PG, Dautry C, Hantraye P, Bloch G . Brain GABA editing without macromolecule contamination. Magn Resonan Med 2001; 45: 517–520.

    Article  CAS  Google Scholar 

  25. Barch DM, Ceaser A . Cognition in schizophrenia: core psychological and neural mechanisms. Trends Cogn Sci 2012; 16: 27–34.

    Article  Google Scholar 

  26. Strauss GP, Keller WR, Buchanan RW, Gold JM, Fischer BA, McMahon RP et al. Next-generation negative symptom assessment for clinical trials: validation of the Brief Negative Symptom Scale. Schizophr Res 2012; 142: 88–92.

    Article  Google Scholar 

  27. Wechsler D . Wechsler Adult Intelligence Scale, 3rd ed. San Antonio, Texas, Psychological Corporation 1997.

  28. Keefe RS, Harvey PD, Goldberg TE, Gold JM, Walker TM, Kennel C et al. Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS). Schizophr Res 2008; 102: 108–115.

    Article  Google Scholar 

  29. Mausbach BT, Bowie CR, Harvey PD, Twamley EW, Goldman SR, Jeste DV et al. Usefulness of the UCSD performance-based skills assessment (UPSA) for predicting residential independence in patients with chronic schizophrenia. J Psychiatr Res 2008; 42: 320–327.

    Article  Google Scholar 

  30. Forbes NF, Carrick LA, McIntosh AM, Lawrie SM . Working memory in schizophrenia: a meta-analysis. Psychol Med 2009; 39: 889–905.

    Article  CAS  Google Scholar 

  31. Lee J, Park S . Working memory impairments in schizophrenia: a meta-analysis. J Abnorm Psychol 2005; 114: 599–611.

    Article  Google Scholar 

  32. Barch DM, Smith E . The cognitive neuroscience of working memory: relevance to CNTRICS and schizophrenia. Biol Psychiatry 2008; 64: 11–17.

    Article  Google Scholar 

  33. Knowles EE, Weiser M, David AS, Dickinson D, Glahn D, Gold J et al. Dedifferentiation and substitute strategy: deconstructing the processing-speed impairment in schizophrenia. Schizophr Res 2012; 142: 129–136.

    Article  Google Scholar 

  34. Dickinson D, Ramsey ME, Gold JM . Overlooking the obvious: a meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Arch Gen Psychiatry 2007; 64: 532–542.

    Article  Google Scholar 

  35. Dickinson D . Digit symbol coding and general cognitive ability in schizophrenia: worth another look? Br J Psychiatry 2008; 193: 354–356.

    Article  Google Scholar 

  36. Bowie CR, Reichenberg A, Patterson TL, Heaton RK, Harvey PD . Determinants of real-world functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms. Am J Psychiatry 2006; 163: 418–425.

    Article  Google Scholar 

  37. Mugler JP 3rd, Brookeman JR . Three-dimensional magnetization-prepared rapid gradient-echo imaging (3D MP RAGE). Magn Reson Med 1990; 15: 152–157.

    Article  Google Scholar 

  38. Edden RA, Puts NAJ, Harris AD, Barker PB, Evans CJ . Gannet: a batch-processing tool for the quantitative analysis of gamma-aminobutyric acid–edited MR spectroscopy spectra. J Magn Reson Imaging 2014; 40: 1445–1452.

    Article  Google Scholar 

  39. Gasparovic C, Song T, Devier D, Bockholt HJ, Caprihan A, Mullins PG et al. Use of tissue water as a concentration reference for proton spectroscopic imaging. Mag Reson Med 2006; 55: 1219–1226.

    Article  CAS  Google Scholar 

  40. Gao F, Edden RA, Li M, Puts NA, Wang G, Liu C et al. Edited magnetic resonance spectroscopy detects an age-related decline in brain GABA levels. NeuroImage 2013; 78: 75–82.

    Article  CAS  Google Scholar 

  41. Epperson CN, O'Malley S, Czarkowski KA, Gueorguieva R, Jatlow P, Sanacora G et al. Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy. Biol Psychiatry 2005; 57: 44–48.

    Article  CAS  Google Scholar 

  42. Cleveland WS, Devlin SJ . Locally weighted regression - an approach to regression-analysis by local fitting. J Am Stat Assoc 1988; 83: 596–610.

    Article  Google Scholar 

  43. Armitage PBG . Statistical Methods in Medical Research. 2nd edn. Blackwell Scientific: Oxford, 1987.

    Google Scholar 

  44. Fisher RA . On the "Probable Error" of a coefficient of correlation deduced from a small sample. Metron 1921; 1: 3–32.

    Google Scholar 

  45. Woods SW . Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry 2003; 64: 663–667.

    Article  CAS  Google Scholar 

  46. Salami A, Eriksson J, Nilsson LG, Nyberg L . Age-related white matter microstructural differences partly mediate age-related decline in processing speed but not cognition. Biochim Biophys Acta 2012; 1822: 408–415.

    Article  CAS  Google Scholar 

  47. Karbasforoushan H, Duffy B, Blackford JU, Woodward ND . Processing speed impairment in schizophrenia is mediated by white matter integrity. Psychol Med 2014; 45: 1–12.

    Google Scholar 

  48. Hines RM, Hines DJ, Houston CM, Mukherjee J, Haydon PG, Tretter V et al. Disrupting the clustering of GABAA receptor alpha2 subunits in the frontal cortex leads to reduced gamma-power and cognitive deficits. Proc Natl Acad Sci USA 2013; 110: 16628–16633.

    Article  CAS  Google Scholar 

  49. Chen CM, Stanford AD, Mao X, Abi-Dargham A, Shungu DC, Lisanby SH et al. GABA level, gamma oscillation, and working memory performance in schizophrenia. NeuroImage Clin 2014; 4: 531–539.

    Article  Google Scholar 

  50. Stan AD, Lewis DA . Altered cortical GABA neurotransmission in schizophrenia: insights into novel therapeutic strategies. Curr Pharm Biotechnol 2012; 13: 1557–1562.

    Article  CAS  Google Scholar 

  51. Kochunov P, Chiappelli J, Wright SN, Rowland LM, Patel B, Wijtenburg SA et al. Multimodal white matter imaging to investigate reduced fractional anisotropy and its age-related decline in schizophrenia. Psychiatry Res 2014; 223: 148–156.

    Article  Google Scholar 

  52. Wright SN, Kochunov P, Chiappelli J, McMahon RP, Muellerklein F, Wijtenburg SA et al. Accelerated white matter aging in schizophrenia: role of white matter blood perfusion. Neurobiol Aging 2014; 35: 2411–2418.

    Article  Google Scholar 

  53. Jeste DV, Wolkowitz OM, Palmer BW . Divergent trajectories of physical, cognitive, and psychosocial aging in schizophrenia. Schizophr Bull 2011; 37: 451–455.

    Article  Google Scholar 

  54. Kirkpatrick B, Messias E, Harvey PD, Fernandez-Egea E, Bowie CR . Is schizophrenia a syndrome of accelerated aging? Schizophr Bull 2008; 34: 1024–1032.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the volunteers, especially the participants with schizophrenia, for participating in the study. This work is supported by National Institutes of Health (T32MH067533, R01MH094520, R01MH085646, R01DA027680, and P50MH103222). We thank Dr. Richard Edden and colleagues who kindly provided GANNET funded through NIH R01 EB016089 and P41 EB015909. We kindly thank Drs. William Carpenter and Juan Bustillo for their comments on this manuscript.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore,, MD, USA

    L M Rowland, B W Krause, S A Wijtenburg, R P McMahon, J Chiappelli, K L Nugent, S J Nisonger, S A Korenic, P Kochunov & L E Hong

  2. Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore,, MD, USA

    L M Rowland

  3. Department of Psychology, University of Maryland Baltimore County, Baltimore,, MD, USA

    L M Rowland

  4. Department of Physics, University of Maryland Baltimore County, Baltimore,, MD, USA

    P Kochunov

Authors
  1. L M Rowland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B W Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S A Wijtenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R P McMahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Chiappelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K L Nugent
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S J Nisonger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S A Korenic
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Kochunov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L E Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L M Rowland.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rowland, L., Krause, B., Wijtenburg, S. et al. Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study. Mol Psychiatry 21, 198–204 (2016). https://doi.org/10.1038/mp.2015.34

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.34

This article is cited by

Search

Advanced search

Quick links