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Annotation

Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X, Gil R, Slifstein M, Abi-Dargham A, Lisanby SH, Shungu DC. Elevated Prefrontal Cortex ?-Aminobutyric Acid and Glutamate-Glutamine Levels in Schizophrenia Measured In Vivo With Proton Magnetic Resonance Spectroscopy. Arch Gen Psychiatry . 2012 Jan 2 ; PubMed Abstract

Comments on Paper and Primary News
Primary News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects

Comment by:  Dost Ongur
Submitted 19 January 2012 Posted 19 January 2012

This news story by Allison Curley cogently and succinctly describes the current state of affairs in studies of parenchymal GABA levels in schizophrenia. Measuring GABA in vivo in the human brain has been challenging because this metabolite exists in relatively low concentration and its signal overlaps with that of other, more abundant metabolites. The literature has grown recently with the advent of higher-field MRI scanners and reliable MRS approaches for GABA measurement.

As outlined in the story, the several papers on parenchymal GABA levels in schizophrenia are about evenly split, with reductions and elevations both being reported. Although MRS is characterized by a relatively low signal-to-noise ratio and high variance in most datasets, all the recent studies used reliable MRS techniques such as MEGAPRESS.

In my opinion, the current state of the literature offers two insights:

1. If there was a significant and consistent abnormality in parenchymal GABA levels in schizophrenia, we would have found it and the studies would agree. Rather, it appears that there...  Read more


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Comment by:  Reiji Yoshimura
Submitted 23 January 2012 Posted 25 January 2012
  I recommend this paper

The GABA theory of schizophrenia is very attractive. I read with much interest the paper from the labs of Lawrence Kegeles and Dikoma Shungu. The authors demonstrated a 30 percent elevation in GABA levels in the medial prefrontal cortex. We previously investigated brain GABA levels in three regions in early-stage, first-episode medicated and unmedicated schizophrenia patients (Goto et al., 2009). GABA was decreased in the left basal ganglia but unchanged in the frontal lobe. We consider the inconsistency of reports regarding brain GABA in schizophrenia to be mainly attributable to methodological issues. An easier and more accurate way to measure brain GABA might confirm the GABA hypothesis of schizophrenia.

References:

Goto N, Yoshimura R, Ueda N, et al. Reduction of brain gamma-aminobutylic acid (GABA) concentrations in early-stage schizophrenia patients: 3T Proton MRS study. Schizophr Res 2009; 112: 192-3. Abstract

View all comments by Reiji Yoshimura


Primary News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects

Comment by:  Jong H. YoonRichard J. Maddock
Submitted 8 February 2012 Posted 8 February 2012

The study by Kegeles et al. has added unique and important findings to the small but rapidly growing literature assessing in-vivo GABA levels in schizophrenia using MRS. In the context of these studies, the Kegeles publication also raises several challenging questions regarding the potential relevance and reliability of in-vivo GABA studies. Here, we would like to comment on two of these questions. The first pertains to the lack of convergence with the consistent postmortem studies. The second is the apparent lack of consistency across the recent in-vivo GABA studies in schizophrenia.

A starting point in the discussion of the first issue is to recognize the differences in what we are measuring with in-vivo spectroscopy as opposed to the postmortem studies. The latter have consistently demonstrated decreased mRNA levels for GAD67, one of the major synthetic enzymes for GABA, in a subset of GABAergic interneurons in the neocortex of schizophrenia. Based on this postmortem work and the important role GAD67 plays in determining whole cell content of GABA (  Read more


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Primary News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects

Comment by:  Robert McCarleyMargaret NiznikiewiczMartina M. VoglmaierKevin Spencer (Disclosure)
Nick Bolo
Alexander P. LinYouji Hirano
Elisabetta del Re
Israel MolinaVicky Liao
Sai Merugumala
Submitted 13 February 2012 Posted 14 February 2012
  I recommend this paper

The important and elegantly controlled work by Kegeles et al., and the informed comments of Ongur, Yoshimura, and Yoon and Maddock, on GABA in schizophrenia raise a series of potentially key factors about the sources of variability of MRS findings in this disorder (medication, stage of illness, and region of interest [ROI]). They also point out the need for association of MRS GABA findings with physiologic measures such as γ oscillations (40 Hz), a functional measure particularly relevant because of the involvement of GABA interneurons interacting with pyramidal neurons in generating this oscillation.

We would like to call the reader's attention to a potentially informative schizophrenia spectrum disorder, schizotypal personality disorder (SPD), that may help shed light on and respond to these issues. As has been documented by Kendler (Kendler et al., 1993; Fanous et al., 2007), SPD shares a genetic relationship with schizophrenia. Although sharing the symptoms of...  Read more


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View all comments by Elisabetta del Re
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View all comments by Sai Merugumala

Primary News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects

Comment by:  Lawrence KegelesDikoma C. Shungu
Submitted 4 April 2012 Posted 5 April 2012

The news story by Allison Curley on our recent paper gives a concise and insightful overview of in-vivo studies of GABA levels in schizophrenia. As the story notes, for those keeping score, studies measuring GABA in schizophrenia are evenly split in that two showed increases, two found decreases, and one reported no change. A major theme running through the thoughtful commentaries by Ongur, Yoshimura, Yoon and Maddock, and McCarley and colleagues is how to understand the variability across studies.

Some regularities can already be found in these and similar studies of the glutamate system. If we confine the scorekeeping to GABA in the prefrontal cortex (PFC), the studies are more uniform: two showed increases (Ongur et al., 2010; Kegeles et al., 2012) and two showed no change (Goto et al., 2009; Tayoshi et al., 2010). If we further limit attention to unmedicated patients, but broaden the...  Read more


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