This is one of the first published studies examining in vivo brain GABA levels in schizophrenia. We found significantly reduced visual cortical GABA in the schizophrenia group. We also found a significant positive correlation between GABA levels and magnitude of OSSS. Taken together, these findings support the GABA deficit hypothesis of cognitive impairments in schizophrenia—that reduced neocortical GABA neurotransmission in schizophrenia leads to impairments in cognitive processes involving inhibition. These results also suggest that relatively simple behavioral tasks such as surround suppression may serve as behavioral assays of inhibitory dysfunction in schizophrenia.
Although our conclusions are derived from measurements of GABA in visual cortex and a task thought to involve visual cortical GABAergic transmission, it is likely that analogous abnormalities generalize to other cortical areas. Histological studies have documented similar deficits in GABAergic markers in a number of cortical regions in schizophrenia (Hashimoto et al., 2008a
). In addition, there is substantial evidence that the morphological subtypes of cortical neurons and their basic laminar and tangential connectivity are conserved across cortical areas (Douglas and Martin, 2004
Our group and others have previously demonstrated impaired visual inhibition in schizophrenia, (Must et al., 2004
; Dakin et al., 2005
; Tadin et al., 2006
; Yoon et al., 2009
). While these prior studies are consistent with the GABA deficit hypothesis, they did not measure GABA concentrations. The present study, by both demonstrating a deficit in GABA concentrations in schizophrenia and a strong association between GABA levels and a behavioral measure of visual inhibition, provides a direct link between GABA dysfunction and cognitive deficits in schizophrenia.
Our finding of reduced GABA is consistent with the animal and post-mortem literature. The GAD67 synthesizes the overwhelming majority of neural GABA (Asada et al., 1997
; Chattopadhyaya et al., 2007
). In schizophrenia, post-mortem studies have documented an approximately 50% reduction in the number of PV+ neurons with detectable levels of GAD67 mRNA in the DLPFC, where PV+ neurons constitute approximately 25% of all GABAergic neurons (Hashimoto et al., 2003
). These results suggest that GAD67 deficits in schizophrenia should translate into measurable reductions in GABA concentration.
A number of studies have addressed issues of sensitivity and validity of MRS measurements of brain GABA. A recent study demonstrated high test-retest reliability of the MEGA-PRESS method, particularly when employing the creatine normalization procedure (Bogner et al., 2009
). Other studies have demonstrated that the MEGA-PRESS method has sufficient sensitivity to detect changes in GABA levels resulting from interventions known to alter GABA concentrations (Verhoeff et al., 1999
; Floyer-Lea et al., 2006
We did not find a group difference in Glx values. Prior studies measuring glutamate or Glx in prefrontal regions have yielded inconsistent results (Theberge et al., 2002
; van Elst et al., 2005
; Ohrmann et al., 2007
; Lutkenhoff et al., 2008
; Galinska et al., 2009
). We are not aware of any MRS studies of glutamate or Glx in visual cortex in schizophrenia. Our Glx results control for generalized measurement error because the potential sources of bias towards finding group differences for Glx are nearly identical to those for GABA, e.g. sensitivity to head movement and differences in the proportions of gray matter within the volume. Equivalent Glx measurements suggest that the group differences in GABA are specific.
Dopamine blocking agents have been shown to lower extracellular levels of GABA (Bourdelais and Deutch, 1994
). While the specific mechanisms are likely complex, with D2 and D1 receptor activation promoting decreased and increased GABA release, respectively (Seamans et al., 2001
), anti-psychotics could be contributing to the lower GABA MRS measurements in subjects with schizophrenia. Several lines of evidence, however, suggest that this may not be the case. Monkey and humans studies have shown similar patterns of GAD67 deficits in subjects with and without exposure to anti-psychotics (Volk et al., 2000
; Hashimoto et al., 2008b
). In our sample, the trend towards the persistence of the group difference in GABA concentration after covarying for medication dosage and the low correlation between anti-psychotic dosage and GABA concentration argue against a significant effect. Nonetheless, future studies testing a larger sample of medication naïve subjects is required to fully address this medication confound.
The fact that surround suppression exhibits selectivity for stimulus orientation for both behavior (Xing and Heeger, 2001
; Yoon et al., 2009
) and V1 neuron responses (Blakemore and Tobin, 1972
; Cavanaugh et al., 2002b
) suggests an early visual cortical locus. In addition, fMRI studies (Zenger-Landolt and Heeger, 2003
) have demonstrated correlates of surround suppression in primary visual cortex. However, the spatial (Angelucci et al., 2002
; Cavanaugh et al., 2002b
) and temporal (Bair et al., 2003
) properties of surround suppression suggest a critical role for feedback projections from extrastriate cortex (Angelucci and Bressloff, 2006
). Because these feedback projections are excitatory, current models propose that they modulate surround suppression via inhibitory GABAergic interneurons (Cavanaugh et al., 2002b
; Schwabe et al., 2006
; Smith, 2006
). These models receive support from intracellular recordings of V1 neurons, in which presentation of a surround stimulus elicited a transient increase in inhibitory conductance followed by a sustained reduction in both excitatory and inhibitory conductance, all of which were orientation-selective (Ozeki et al., 2009
A previous study assessed the effects of local iontophoresis of the GABAA receptor antagonist bicuculline on surround suppression (Ozeki et al., 2004
). Bicuculline reduced the magnitude of surround suppression of individual V1 neuronal responses approximately 12%. However, it is difficult to interpret the effects of local changes in inhibition, as surround suppression likely involves circuits outside the region of drug administration. In contrast, we measured global GABA concentrations in visual cortex and demonstrated its strong correlation with the magnitude of OSSS.
An important issue not addressed by this study is the primacy of GABA deficits in schizophrenia, particularly in reference to glutamatergic dysfunction. Some have proposed that GABA abnormalities are downstream effects of impaired NMDA receptor-mediated neurotransmission which results in reduced glutamatergic drive on activity-dependent GABA synthesis. (Lewis and Gonzalez-Burgos, 2006
In summary, we found reduced GABA concentrations in the visual cortex of subjects with schizophrenia. GABA concentrations were highly correlated with a behavioral measure of visual inhibition, such that higher GABA concentration predicted greater OSSS. These findings provide the first in vivo evidence of a deficit in cortical GABA in schizophrenia and support the GABA deficit hypothesis of cognitive deficits in this disorder. Further study of the GABA system is likely to provide important insights into the neural mechanisms of these cognitive deficits.