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1.  Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex 
The Journal of Physiology  2011;589(23):5845-5855.
Non-technical summary
Inter-individual differences in regional GABA as assessed by magnetic resonance spectroscopy (MRS) relate to behavioural variation in humans. However, it is not clear what the relationship is between MRS measures of the concentration of neurotransmitters in a region and synaptic activity. Transcranial magnetic stimulation (TMS) techniques provide physiological measures of cortical excitation or inhibition. Here, we investigated the relationship between MRS and TMS measures of glutamatergic and GABAergic activity within the same individuals. We demonstrated a relationship between MRS-assessed glutamate levels and a TMS measure of global cortical excitability, suggesting that MRS measures of glutamate do reflect glutamatergic activity. However, there was no clear relationship between MRS-assessed GABA levels and TMS measures of synaptic GABAA or GABAB activity. A relationship was found between MRS-assessed GABA and a TMS protocol with less clearly understood physiological underpinnings. We speculate that this protocol may therefore reflect extrasynaptic GABA tone.
Abstract
Magnetic resonance spectroscopy (MRS) allows measurement of neurotransmitter concentrations within a region of interest in the brain. Inter-individual variation in MRS-measured GABA levels have been related to variation in task performance in a number of regions. However, it is not clear how MRS-assessed measures of GABA relate to cortical excitability or GABAergic synaptic activity. We therefore performed two studies investigating the relationship between neurotransmitter levels as assessed by MRS and transcranial magnetic stimulation (TMS) measures of cortical excitability and GABA synaptic activity in the primary motor cortex. We present uncorrected correlations, where the P value should therefore be considered with caution. We demonstrated a correlation between cortical excitability, as assessed by the slope of the TMS input–output curve and MRS-assessed glutamate levels (r = 0.803, P = 0.015) but no clear relationship between MRS-assessed GABA levels and TMS-assessed synaptic GABAA activity (2.5 ms inter-stimulus interval (ISI) short-interval intracortical inhibition (SICI); Experiment 1: r = 0.33, P = 0.31; Experiment 2: r =–0.23, P = 0.46) or GABAB activity (long-interval intracortical inhibition (LICI); Experiment 1: r =–0.47, P = 0.51; Experiment 2: r = 0.23, P = 0.47). We demonstrated a significant correlation between MRS-assessed GABA levels and an inhibitory TMS protocol (1 ms ISI SICI) with distinct physiological underpinnings from the 2.5 ms ISI SICI (r =–0.79, P = 0.018). Interpretation of this finding is challenging as the mechanisms of 1 ms ISI SICI are not well understood, but we speculate that our results support the possibility that 1 ms ISI SICI reflects a distinct GABAergic inhibitory process, possibly that of extrasynaptic GABA tone.
doi:10.1113/jphysiol.2011.216978
PMCID: PMC3249054  PMID: 22005678
2.  Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex 
The Journal of Physiology  2011;589(Pt 23):5845-5855.
Non-technical summary
Inter-individual differences in regional GABA as assessed by magnetic resonance spectroscopy (MRS) relate to behavioural variation in humans. However, it is not clear what the relationship is between MRS measures of the concentration of neurotransmitters in a region and synaptic activity. Transcranial magnetic stimulation (TMS) techniques provide physiological measures of cortical excitation or inhibition. Here, we investigated the relationship between MRS and TMS measures of glutamatergic and GABAergic activity within the same individuals. We demonstrated a relationship between MRS-assessed glutamate levels and a TMS measure of global cortical excitability, suggesting that MRS measures of glutamate do reflect glutamatergic activity. However, there was no clear relationship between MRS-assessed GABA levels and TMS measures of synaptic GABAA or GABAB activity. A relationship was found between MRS-assessed GABA and a TMS protocol with less clearly understood physiological underpinnings. We speculate that this protocol may therefore reflect extrasynaptic GABA tone.
Abstract
Magnetic resonance spectroscopy (MRS) allows measurement of neurotransmitter concentrations within a region of interest in the brain. Inter-individual variation in MRS-measured GABA levels have been related to variation in task performance in a number of regions. However, it is not clear how MRS-assessed measures of GABA relate to cortical excitability or GABAergic synaptic activity. We therefore performed two studies investigating the relationship between neurotransmitter levels as assessed by MRS and transcranial magnetic stimulation (TMS) measures of cortical excitability and GABA synaptic activity in the primary motor cortex. We present uncorrected correlations, where thePvalue should therefore be considered with caution. We demonstrated a correlation between cortical excitability, as assessed by the slope of the TMS input–output curve and MRS-assessed glutamate levels (r = 0.803, P = 0.015) but no clear relationship between MRS-assessed GABA levels and TMS-assessed synaptic GABAA activity (2.5 ms inter-stimulus interval (ISI) short-interval intracortical inhibition (SICI); Experiment 1:r = 0.33, P = 0.31; Experiment 2:r = –0.23, P = 0.46) or GABAB activity (long-interval intracortical inhibition (LICI); Experiment 1:r = –0.47, P = 0.51; Experiment 2:r = 0.23, P = 0.47). We demonstrated a significant correlation between MRS-assessed GABA levels and an inhibitory TMS protocol (1 ms ISI SICI) with distinct physiological underpinnings from the 2.5 ms ISI SICI (r = –0.79, P = 0.018). Interpretation of this finding is challenging as the mechanisms of 1 ms ISI SICI are not well understood, but we speculate that our results support the possibility that 1 ms ISI SICI reflects a distinct GABAergic inhibitory process, possibly that of extrasynaptic GABA tone.
doi:10.1113/jphysiol.2011.216978
PMCID: PMC3249054  PMID: 22005678
3.  The Impact of Gabapentin Administration on Brain GABA and Glutamate Concentrations: A 7T 1H-MRS Study 
Neuropsychopharmacology  2012;37(13):2764-2771.
Gamma-aminobutyric acid (GABA) and glutamate are implicated in numerous neuropsychiatric and substance abuse conditions, but their spectral overlap with other resonances makes them a challenge to quantify in humans. Gabapentin, marketed for the treatment of seizures and neuropathic pain, has been shown to increase in vivo GABA concentration in the brain of both rodents and humans. Gabapentin effects on glutamate are not known. We conducted a gabapentin (900 mg) challenge in healthy human subjects to confirm and explore its effects on GABA and glutamate concentrations, respectively, and to test the ability of single voxel localized proton magnetic resonance spectroscopy (1H-MRS) to reliably measure GABA and glutamate in the visual cortex at the ultra-high magnetic field of 7 Tesla. Reproducibility of GABA and glutamate measurements was determined in a comparison group without drug twice within day and 2 weeks apart. Although GABA concentration changes were small both within day (average 5.6%) and between day (average 4.8%), gabapentin administration was associated with an average increase in GABA concentration of 55.7% (6.9–91.0%). Importantly, drug-induced change in GABA levels was inversely correlated to the individual's baseline GABA level (R2=0.72). Mean glutamate concentrations did not change significantly with or without drug administration. In conclusion, localized 1H-MRS at 7 Tesla can be successfully applied to the measurement of GABA concentration and is sensitive to acute drug-induced changes in cortical GABA. Whether baseline GABA concentrations predict clinical efficacy of gabapentin is an area worthy of exploration.
doi:10.1038/npp.2012.142
PMCID: PMC3499716  PMID: 22871916
gabapentin; 7 Tesla; γ-aminobutyric acid; GABA; glutamate; Glu; 1H-MRS; GABA; gabapentin; glutamate; imaging; clinical or preclinical; magnetic resonance spectroscopy; psychopharmacology; visual cortex
4.  Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants 
Evidence suggesting that central nervous system γ-aminobutyric acid (GABA) concentrations are reduced in patients with major depressive disorder (MDD) has been present since at least 1980, and this idea has recently gained support from more recent magnetic resonance spectroscopy data. These observations have led to the assumption that MDD’s underlying etiology is tied to an overall reduction in GABA-mediated inhibitory neurotransmission. In this paper, we review the mechanisms that govern GABA and glutamate concentrations in the brain, and provide a comprehensive and critical evaluation of the clinical data supporting reduced GABA neurotransmission in MDD. This review includes an evaluation of magnetic resonance spectroscopy data, as well as data on the expression and function of the GABA-synthesizing enzyme glutamic acid decarboxylase, GABA neuron-specific cell markers, such as parvalbumin, calretinin and calbindin, and the GABAA and GABAB receptors in clinical MDD populations. We explore a potential role for glial pathology in MDD-related reductions in GABA concentrations, and evidence of a connection between neurosteroids, GABA neurotransmission, and hormone-related mood disorders. Additionally, we investigate the effects of GABAergic pharmacological agents on mood, and demonstrate that these compounds have complex effects that do not universally support the idea that reduced GABA neurotransmission is at the root of MDD. Finally, we discuss the connections between serotonergic and GABAergic neurotransmission, and show that two serotonin-focused antidepressants – the selective serotonin-reuptake inhibitor fluoxetine and the multimodal antidepressant vortioxetine – modulate GABA neurotransmission in opposing ways, despite both being effective MDD treatments. Altogether, this review demonstrates that there are large gaps in our understanding of the relationship between GABA physiology and MDD, which must be remedied with more data from well-controlled empirical studies. In conclusion, this review suggests that the simplistic notion that MDD is caused by reduced GABA neurotransmission must be discarded in favor of a more nuanced and complex model of the role of inhibitory neurotransmission in MDD.
doi:10.2147/DDDT.S62912
PMCID: PMC4307650  PMID: 25653499
GABA; major depressive disorder; serotonin; 5-HT
5.  GABA and glutamate in schizophrenia: A 7 T 1H-MRS study 
NeuroImage : Clinical  2014;6:398-407.
Schizophrenia is characterized by loss of brain volume, which may represent an ongoing pathophysiological process. This loss of brain volume may be explained by reduced neuropil rather than neuronal loss, suggesting abnormal synaptic plasticity and cortical microcircuitry. A possible mechanism is hypofunction of the NMDA-type of glutamate receptor, which reduces the excitation of inhibitory GABAergic interneurons, resulting in a disinhibition of glutamatergic pyramidal neurons. Disinhibition of pyramidal cells may result in excessive stimulation by glutamate, which in turn could cause neuronal damage or death through excitotoxicity.
In this study, GABA/creatine ratios, and glutamate, NAA, creatine and choline concentrations in the prefrontal and parieto-occipital cortices were measured in 17 patients with schizophrenia and 23 healthy controls using proton magnetic resonance spectroscopy at an ultra-high magnetic field strength of 7 T. Significantly lower GABA/Cr ratios were found in patients with schizophrenia in the prefrontal cortex as compared to healthy controls, with GABA/Cr ratios inversely correlated with cognitive functioning in the patients. No significant change in the GABA/Cr ratio was found between patients and controls in the parieto-occipital cortex, nor were levels of glutamate, NAA, creatine, and choline differed in patients and controls in the prefrontal and parieto-occipital cortices. Our findings support a mechanism involving altered GABA levels distinguished from glutamate levels in the medial prefrontal cortex in schizophrenia, particularly in high functioning patients. A (compensatory) role for GABA through altered inhibitory neurotransmission in the prefrontal cortex may be ongoing in (higher functioning) patients with schizophrenia.
Highlights
•GABA and glutamate were measured in schizophrenia patients and healthy controls using 1H-MRS at 7 T.•Patients showed significantly lower prefrontal GABA levels, and no changes were found for glutamate.•Prefrontal GABA levels were inversely correlated with total IQ in patients.•This suggests a mechanism involving GABA distinguished from glutamate in the prefrontal cortex.•GABA may have a compensatory role in the prefrontal cortex in (higher functioning) patients.
doi:10.1016/j.nicl.2014.10.005
PMCID: PMC4218940  PMID: 25379453
Schizophrenia; GABA; Glutamate; 1H-MRS; 7 T
6.  Gamma-Aminobutyric Acid Concentration is Reduced in Visual Cortex in Schizophrenia and Correlates with Orientation-Specific Surround Suppression 
The neural mechanisms underlying cognitive deficits in schizophrenia remain largely unknown. The gamma-aminobutyric acid (GABA) hypothesis proposes that reduced neuronal GABA concentration and neurotransmission results in cognitive impairments in schizophrenia. However, few in vivo studies have directly examined this hypothesis. We employed magnetic resonance spectroscopy (MRS) at high field to measure visual cortical GABA levels in 13 subjects with schizophrenia and 13 demographically matched healthy control subjects. We found that the schizophrenia group had an approximately 10% reduction in GABA concentration. We further tested the GABA hypothesis by examining the relationship between visual cortical GABA levels and orientation-specific surround suppression (OSSS), a behavioral measure of visual inhibition thought to be dependent on GABAergic synaptic transmission. Previous work has shown that subjects with schizophrenia exhibit reduced OSSS of contrast discrimination (Yoon et al., 2009). For subjects with both MRS and OSSS data (n=16), we found a highly significant positive correlation (r=0.76) between these variables. GABA concentration was not correlated with overall contrast discrimination performance for stimuli without a surround (r=-0.10). These results suggest that a neocortical GABA deficit in subjects with schizophrenia leads to impaired cortical inhibition and that GABAergic synaptic transmission in visual cortex plays a critical role in OSSS.
doi:10.1523/JNEUROSCI.6158-09.2010
PMCID: PMC2846788  PMID: 20220012
surround suppression; inhibition; schizophrenia; GABA; visual processing; cognitive deficits
7.  Relating MEG Measured Motor Cortical Oscillations to resting γ-Aminobutyric acid (GABA) Concentration 
NeuroImage  2011;55(2):616-621.
The human motor cortex exhibits characteristic beta (15-30 Hz) and gamma oscillations (60-90 Hz), typically observed in the context of transient finger movement tasks. The functional significance of these oscillations, such as post-movement beta rebound (PMBR) and movement-related gamma synchrony (MRGS) remain unclear. Considerable animal and human non-invasive studies, however, suggest that the networks supporting these motor cortex oscillations depend critically on the inhibitory neurotransmitter γ-Aminobutyric acid (GABA). Despite such speculation, a direct relation between MEG measured motor cortex oscillatory power and frequency with resting GABA concentrations has not been demonstrated.
In the present study, motor cortical responses were measured from 9 healthy adults while they performed a cued button-press task using their right index finger. In each participant, PMBR and MRGS measures were obtained from time-frequency plots obtained from primary motor (MI) sources, localized using beamformer differential source localization. For each participant, complimentary magnetic resonance spectroscopy (MRS) GABA measures aligned to the motor hand knob of the left central sulcus were also obtained. GABA concentration was estimated as the ratio of the motor cortex GABA integral to a cortical reference NAA resonance at 2 ppm.
A significant linear relation was observed between MI GABA concentration and MRGS frequency (R2 = 0.46, p<0.05), with no association observed between GABA concentration and MRGS power. Conversely, a significant linear relation was observed between MI GABA concentration and PMBR power (R2 = 0.34, p<0.05), with no relation observed for GABA concentration and PMBR frequency. Finally, a significant negative linear relation between the participant’s age and MI gamma frequency was observed, such that older participants had a lower gamma frequency (R2 = 0.40, p < 0.05).
Present findings support a role for GABA in the generation and modulation of endogenous motor cortex rhythmic beta and gamma activity.
doi:10.1016/j.neuroimage.2010.12.077
PMCID: PMC3411117  PMID: 21215806
Magnetic Resonance Spectroscopy (MRS); γ-Aminobutyric acid (GABA); Event-related desynchrony / synchrony (ERD/ERS)
8.  Increased GABA Contributes to Enhanced Control over Motor Excitability in Tourette Syndrome 
Current Biology  2014;24(19):2343-2347.
Summary
Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4–7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8–11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of γ-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)—a region strongly associated with the genesis of motor tics in TS [14]—are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics.
Highlights
•We report a 7 T 1H MRS investigation of GABA in Tourette syndrome (TS)•GABA levels within the SMA are significantly elevated in TS•SMA GABA is negatively correlated with SMA BOLD and cortical excitability•SMA GABA is predicted by motor tic severity and corpus callosum FA values
Using magnetic resonance spectroscopy, Draper et al. find that concentrations of the neurotransmitter GABA in motor areas of the brain are associated with symptom severity in individuals with Tourette syndrome.
doi:10.1016/j.cub.2014.08.038
PMCID: PMC4188813  PMID: 25264251
9.  Local GABA concentration is related to network-level resting functional connectivity 
eLife  2014;3:e01465.
Anatomically plausible networks of functionally inter-connected regions have been reliably demonstrated at rest, although the neurochemical basis of these ‘resting state networks’ is not well understood. In this study, we combined magnetic resonance spectroscopy (MRS) and resting state fMRI and demonstrated an inverse relationship between levels of the inhibitory neurotransmitter GABA within the primary motor cortex (M1) and the strength of functional connectivity across the resting motor network. This relationship was both neurochemically and anatomically specific. We then went on to show that anodal transcranial direct current stimulation (tDCS), an intervention previously shown to decrease GABA levels within M1, increased resting motor network connectivity. We therefore suggest that network-level functional connectivity within the motor system is related to the degree of inhibition in M1, a major node within the motor network, a finding in line with converging evidence from both simulation and empirical studies.
DOI: http://dx.doi.org/10.7554/eLife.01465.001
eLife digest
Even when your body is at rest, your brain remains active. Subjects lying in brain scanners without any specific task to perform show coordinated and reproducible patterns of brain activity. Areas of the brain with similar functions, such as those involved in vision or in movement, tend to increase or decrease their activity in sync, and these coordinated patterns are referred to as resting state networks.
The functions of these networks are unclear—they may support introspection, memory recall or planning for the future, or they may help to strengthen newly acquired skills by enabling the brain to replay previous learning episodes. There is evidence that resting state networks are altered in disorders such as Alzheimer’s disease, autism and schizophrenia, but little is known about how these changes arise or what they might mean.
Now, Stagg et al. have used a type of brain scan called magnetic resonance spectroscopy to gain insights into the mechanisms by which one particular network—the resting motor network—is generated. This network consists of areas involved in planning, monitoring and executing movements, and includes the primary motor cortex, which initiates movements by sending instructions to the spinal cord.
The levels of a chemical called GABA—a neurotransmitter molecule that tends to inhibit the activity of nerve cells—were measured in the primary motor cortex of young healthy volunteers as they lay idle in a scanner. GABA levels were negatively correlated with the amount of coordinated activity within the resting motor network. By contrast, no relation was seen between coordinated activity and the levels of the neurotransmitter glutamate, which tends to increase the activity of nerve cells. Furthermore, when a weak electric current was applied through the subjects’ scalp to their primary motor cortex—a technique previously shown to lower levels of GABA in the region—the resting motor network became stronger.
In addition to providing new information on how the rhythmic patterns of activity seen in the resting brain arise, the work of Stagg et al. contributes to the more general effort to understand the complex patterns of connections within the human brain.
DOI: http://dx.doi.org/10.7554/eLife.01465.002
doi:10.7554/eLife.01465
PMCID: PMC3964822  PMID: 24668166
magnetic resonance spectroscopy; GABA; resting state fMRI; human
10.  Reduced GABA Concentration in Attention-Deficit/Hyperactivity Disorder 
Archives of general psychiatry  2012;69(7):750-753.
Context
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a deficit in behavioral inhibition. Recent evidence also suggests a deficit in cortical inhibition via the GABA (γ-aminobutyric acid)–ergic system.
Objective
To investigate the GABAergic component of ADHD using magnetic resonance spectroscopy.
Design
Cross-sectional study.
Setting
Participants were recruited through local schools, local pediatric and other community clinics, and through advertisement in regional publications. Magnetic resonance spectroscopy was performed within the research institute.
Participants
Children (age range, 8–12 years) in a typically developing control group vs a group with ADHD were compared.
Main Outcome Measures
J-difference–edited magnetic resonance spectroscopy at 3 T was used to measure GABA concentration in a volume that included primary somatosensory and motor cortices.
Results
GABA concentration is reduced in children with ADHD compared with typically developing control subjects.
Conclusion
Our finding of reduced GABA concentration in ADHD is concordant with recently reported deficits in short intracortical inhibition in ADHD and suggests a GABAergic deficit in ADHD.
doi:10.1001/archgenpsychiatry.2011.2280
PMCID: PMC3970207  PMID: 22752239
11.  GABA level, gamma oscillation, and working memory performance in schizophrenia 
NeuroImage : Clinical  2014;4:531-539.
A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case–control pilot study (N = 24) compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs) to GABA levels measured in vivo with magnetic resonance spectroscopy. Working memory performance, baseline GABA level in the left dorsolateral prefrontal cortex (DLPFC), and measures of gamma oscillations from EEGs at baseline and during a working memory task were obtained. A major limitation of this study is a relatively small sample size for several analyses due to the integration of diverse methodologies and participant compliance. Working memory performance was significantly lower for patients than for controls. During the working memory task, patients (n = 7) had significantly lower amplitudes in gamma oscillations than controls (n = 9). However, both at rest and across working memory stages, there were significant correlations between gamma oscillation amplitude and left DLPFC GABA level. Peak gamma frequency during the encoding stage of the working memory task (n = 16) significantly correlated with GABA level and working memory performance. Despite gamma band amplitude deficits in patients across working memory stages, both baseline and working memory-induced gamma oscillations showed strong dependence on baseline GABA levels in patients and controls. These findings suggest a critical role for GABA function in gamma band oscillations, even under conditions of system and cognitive impairments as seen in schizophrenia.
Highlights
•We compared in vivo GABA measures and gamma band oscillations in schizophrenia.•Correlations between left DLPFC GABA and gamma amplitude were significant.•Peak gamma frequency significantly correlated with GABA and performance.•Patients had significantly lower amplitudes in gamma oscillations than controls.•Working memory performance was significantly lower for patients than for controls.
doi:10.1016/j.nicl.2014.03.007
PMCID: PMC3989525  PMID: 24749063
Schizophrenia; Magnetic resonance spectroscopy; GABA; Gamma oscillation; Dorsolateral prefrontal cortex; Working memory
12.  Elevated Endogenous GABA Concentration Attenuates Glutamate-Glutamine Cycling between Neurons and Astroglia 
In this study, the relationship between endogenous brain GABA concentration and glutamate-glutamine cycling flux (Vcyc) was investigated using in vivo 1H and 1H{13C} magnetic resonance spectroscopy techniques. Graded elevations of brain GABA levels were induced in rat brain after administration of the highly specific GABA-transaminase inhibitor vigabatrin (γ-vinyl-GABA). The glial-specific substrate [2-13C]acetate and 1H{13C} magnetic resonance spectroscopy were used to measure Vcyc at different GABA levels. Significantly reduced Vcyc was found in rats pretreated with vigabatrin. The reduction in group mean Vcyc over the range of GABA concentrations investigated in this study (1.0 ± 0.3 ~ 5.1 ± 0.5 μmol/g) was found to be nonlinear: ΔVcyc/Vcyc = [GABA (μmol/g)]−0.35 − 1.0 (r2 = 0.98). The results demonstrate that Vcyc is modulated by endogenous GABA levels, and that glutamatergic and GABAergic interactions can be studied in vivo using noninvasive magnetic resonance spectroscopy techniques.
doi:10.1007/s00702-009-0186-0
PMCID: PMC2845912  PMID: 19184333
GABA; vigabatrin; glutamate; magnetic resonance spectroscopy
13.  Glutamate, GABA, and Other Cortical Metabolite Concentrations during Early Abstinence from Alcohol and their Associations with Neurocognitive Changes* 
Drug and alcohol dependence  2012;125(1-2):27-36.
BACKGROUND
Little is known about the effects of alcohol dependence on cortical concentrations of glutamate (Glu) or gamma aminobutyric acid (GABA). We used proton magnetic resonance spectroscopy (MRS) to study cross-sectionally and longitudinally the concentrations of these Glu and GABA in alcohol dependent individuals (ALC) during early abstinence from alcohol.
Methods
Twenty ALC were studied at about one week of abstinence from alcohol (baseline) and 36 ALC at five weeks of abstinence and compared to 16 light/non-drinking controls (LD). Eleven ALC were studied twice during abstinence. Participants underwent clinical interviewing, blood work, neuropsychological testing, structural imaging and single-volume proton MRS at 4 Tesla. Absolute concentrations of Glu, GABA and those of other 1H MRS-detectable metabolites were measured in the anterior cingulate (ACC), parieto-occipital cortex (POC) and dorso-lateral prefrontal cortex (DLPFC). Relationships of metabolite levels to drinking severity and neurocognition were also assessed.
Results
ALC at baseline had lower concentrations of Glu, N-acetylaspartate (NAA), and choline- (Cho) and creatine-containing metabolites than LD in the ACC, but normal GABA and myo-inositol (mI) levels. At five weeks of abstinence, metabolite concentrations were not significantly different between groups. Between one and five weeks of abstinence, Glu, NAA and Cho levels in the ACC increased significantly. Higher cortical mI concentrations in ALC related to worse neurocognitive outcome.
Conclusion
These MRS data suggest compromised and regionally specific bioenergetics/metabolism in one-week-abstinent ALC that largely normalizes over four weeks of sustained abstinence. The correlation between mI levels and neurocognition affirms the functional relevance of this putative astrocyte marker.
doi:10.1016/j.drugalcdep.2012.03.012
PMCID: PMC3419314  PMID: 22503310
anterior cingulate cortex; glutamate; GABA; abstinence from alcohol; MR spectroscopy
14.  Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency 
Neurology  2009;73(6):423-429.
Objective:
Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism characterized by elevated levels of GABA and gamma-hydroxybutyric acid. Clinical findings include intellectual impairment, hypotonia, hyporeflexia, hallucinations, autistic behaviors, and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model demonstrate use-dependent downregulation of GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utilizing [11C]-flumazenil (FMZ)-PET.
Methods:
FMZ binding was measured in 7 patients, 10 unaffected parents, and 8 healthy controls. Data analysis was performed using a reference region compartmental model, with time-activity curve from pons as the input function. Relative parametric binding potential (BPND) was derived, with MRI-based pixel by pixel partial volume correction, in regions of interest drawn on coregistered MRI.
Results:
In amygdala, hippocampus, cerebellar vermis, frontal, parietal, and occipital cortex, patients with SSADH deficiency had significant reductions in FMZ BPND compared to parents and controls. Mean cortical values were 6.96 ± 0.79 (controls), 6.89 ± 0.71 (parents), and 4.88 ± 0.77 (patients) (F ratio 16.1; p < 0.001). There were no differences between controls and parents in any cortical region.
Conclusions:
Succinic semialdehyde dehydrogenase (SSADH) deficient patients show widespread reduction in BZPR binding on [11C]-flumazenil-PET. Our results suggest that high endogenous brain GABA levels in SSADH deficiency downregulate GABA(A)-BZPR binding site availability. This finding suggests a potential mechanism for neurologic dysfunction in a serious neurodevelopmental disorder, and suggests that PET may be useful to translate studies in animal models to human disease.
GLOSSARY
= flumazenil;
= magnetic resonance spectroscopy;
= partial volume correction;
= region of interest;
= spoiled gradient recall;
= succinic semialdehyde dehydrogenase.
doi:10.1212/WNL.0b013e3181b163a5
PMCID: PMC2727143  PMID: 19667317
15.  Regulation of cortical microcircuits by unitary GABAergic volume transmission 
Nature  2009;461(7268):1278-1281.
Gamma-aminobutyric acid (GABA) is predominantly released by local interneurons in the cerebral cortex to particular subcellular domains of the target cells1,2. This suggests that compartmentalized, synapse specific action of GABA is required in cortical networks for phasic inhibition2–4. However, GABA released at the synaptic cleft diffuses to receptors outside the postsynaptic density and thus tonically activates extrasynaptic GABAA and GABAB receptors, which include subtypes of both receptor families especially sensitive to low concentrations of GABA3–7. The synaptic and extrasynaptic action of GABA is in line with idea that neurons of the brain use synaptic (or wiring) transmission and nonsynaptic (or volume) transmission for communication8,9. However, reuptake mechanisms restrict the spatial extent of extrasynaptic GABAergic effects10,11 and it was proposed that concerted action of several presynaptic interneurons or sustained firing of individual cells or increased release site density is required to reach ambient GABA levels sufficient to activate extrasynaptic receptors4,9,11–13. Here we show that individual neurogliaform cells release GABA sufficient for volume transmission within the axonal cloud and thus neurogliaform cells do not require synapses to produce inhibitory responses in the overwhelming majority of nearby neurons. Neurogliaform cells suppress connections between other neurons acting on presynaptic terminals which do not receive synapses at all in the cerebral cortex and, moreover, reach extrasynaptic, δ subunit containing GABAA (GABAAδ) receptors responsible for tonic inhibition. We reveal that GABAAδ receptors are localized to neurogliaform cells preferentially among cortical interneurons. Neurosteroids, which are modulators of GABAAδ receptors, alter unitary GABAergic effects between neurogliaform cells. In contrast to the specifically placed synapses formed by other interneurons, the output of neurosteroid sensitive neurogliaform cells represents the ultimate form of spatial unspecificity in GABAergic systems leading to long lasting network hyperpolarization combined with widespread suppression of communication in the local circuit.
doi:10.1038/nature08503
PMCID: PMC2771344  PMID: 19865171
16.  Resting-State Glutamate and GABA Concentrations Predict Task-Induced Deactivation in the Default Mode Network 
The Journal of Neuroscience  2013;33(47):18566-18573.
Deactivation of the human brain's default mode network (DMN) is regarded as suppression of endogenous activity to support exogenous task-related processes. This phenomenon has important functional relevance and insufficient DMN deactivation has been implicated in several neuropsychiatric disorders. However, the neurochemical mechanism of the DMN′s deactivation remains largely unknown. In the present study, we test the hypothesis that the major excitatory and inhibitory neurotransmitters, glutamate and GABA, respectively, are associated with DMN deactivation. We used magnetic resonance spectroscopy to measure neurotransmitter concentrations in the posterior cingulate cortex/precuneus (PCC/PCu), a key component of the DMN, and functional magnetic resonance imaging to evaluate DMN deactivation induced by an n-back working memory task. Our results demonstrate significant associations of glutamate and GABA with DMN deactivation. Specifically, high regional GABA concentration in the PCC/PCu area is associated with enhanced deactivation induced by the task in the same region, whereas high glutamate concentration is associated with reduced deactivation. Furthermore, the association between GABA and DMN deactivation increases with the cognitive loads. These neurochemical characteristics of DMN deactivation may provide novel insights toward better understanding of the DMN′s functions under normal physiological conditions and dysfunctions in neuropsychiatric disorders.
doi:10.1523/JNEUROSCI.1973-13.2013
PMCID: PMC3834059  PMID: 24259578
17.  Posteromedial cortexglutamate and GABApredict intrinsic functional connectivity of the default mode network 
NeuroImage  2012;64:112-119.
The balance between excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons determines the function of cortical microcircuits. How these neurotransmitters relate to the functional status of an entire macro-scale network remains unknown. The posteromedial cortex (PMC) is the default mode network (DMN) node with the greatest functional connectivity; therefore, we hypothesized that PMC glutamate and GABA predict intrinsic functional connectivity (iFC) across the DMN. In 20 healthy men, we combined J-resolved magnetic resonance spectroscopy to measure glutamate and GABA in the PMC and resting fMRI followed by group Independent Components Analysis to extract the DMN. We showed that, controlling for age and GM volume in the MRS voxel, PMC glutamate and GABA explained about half of the variance in DMN iFC (represented by the network’s beta coefficient for rest). Glutamate correlated positively and GABA correlated negatively with DMN iFC; in an alternative statistical model which included the glutamate/GABA ratio, the ratio correlated positively with DMN iFC. Age had no independent effect on DMN iFC. No other network was associated with PMC glutamate or GABA. We conclude that regional neurotransmitter concentrations in a network node strongly predict network but not global brain iFC.
doi:10.1016/j.neuroimage.2012.09.029
PMCID: PMC3801193  PMID: 23000786
Default Mode Network; Excitation; Inhibition; Microcircuit; Brain network; Connectivity; precuneus
18.  Regionally Specific Human GABA Concentration Correlates with Tactile Discrimination Thresholds 
The Journal of Neuroscience  2011;31(46):16556-16560.
The neural mechanisms underlying variability in human sensory perception remain incompletely understood. In particular, few studies have attempted to investigate the relationship between in vivo measurements of neurochemistry and individuals’ behavioral performance. Our previous work found a relationship between GABA concentration in the visual cortex and orientation discrimination thresholds (Edden et al., 2009). In the present study, we used magnetic resonance spectroscopy of GABA and psychophysical testing of vibrotactile frequency thresholds to investigate whether individual differences in tactile frequency discrimination performance are correlated with GABA concentration in sensorimotor cortex. Behaviorally, individuals showed a wide range of discrimination thresholds ranging from 3 to 7.6 Hz around the 25 Hz standard. These frequency discrimination thresholds were significantly correlated with GABA concentration (r = −0.58; p < 0.05) in individuals’ sensorimotor cortex, but not with GABA concentration in an occipital control region (r = −0.04). These results demonstrate a link between GABA concentration and frequency discrimination in vivo, and support the hypothesis that GABAergic mechanisms have an important role to play in sensory discrimination.
doi:10.1523/JNEUROSCI.4489-11.2011
PMCID: PMC3374929  PMID: 22090482
19.  Anterior Insula GABA Levels Correlate with Emotional Aspects of Empathy: A Proton Magnetic Resonance Spectroscopy Study 
PLoS ONE  2014;9(11):e113845.
Background:
Empathy is a multidimensional construct referring to the capacity to understand and share the emotional and affective states of another person. Cerebral γ-aminobutyric acid (GABA)-ergic levels are associated with a variety of neurological and psychiatric disorders. However, the role of the GABA system in different dimensions of empathy has not been investigated.
Materials and Methods:
Thirty-two right-handed healthy volunteers took part in this study. We used proton magnetic resonance spectroscopy to determine GABA concentrations in the anterior insula (AI) and the anterior cingulate cortex (ACC) and to examine the relationship between the GABA concentrations and the subcomponents of empathy evaluated by the Interpersonal Reactivity Index (IRI).
Result:
Pearson correlation analyses (two-tailed) showed that AI GABA was significantly associated with the empathy concern score (r = 0.584, p<0.05) and the personal distress score (r = 0.538, p<0.05) but not significantly associated with other empathy subscales. No significant correlation was found between ACC GABA and empathy subscores.
Conclusion:
Left AI GABA was positively correlated with the emotional aspects of empathy. These preliminary findings call into question whether AI GABA alterations might predict empathy dysfunction in major psychiatric disorders such as autism and schizophrenia, which have been described as deficits in emotional empathic abilities.
doi:10.1371/journal.pone.0113845
PMCID: PMC4242717  PMID: 25419976
20.  tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: A 7 T magnetic resonance spectroscopy study 
Neuroimage  2014;99(100):237-243.
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and ‘supervised’ learning of internal ‘forward’ models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.
Highlights
•Ultra-high-field (7 T) magnetic resonance spectroscopy study of the effects of tDCS.•Anodal tDCS leads to a polarity and site specific reduction in MRS-GABA.•tDCS-induced changes in MRS-GABA in M1 predict model-based motor learning/memory.
doi:10.1016/j.neuroimage.2014.05.070
PMCID: PMC4121086  PMID: 24904994
BOLD, blood-oxygen-level-dependent; fMRI, functional magnetic resonance imaging; GABA, γ-amino-butyric acid; M1, primary motor cortex; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N-acetylaspartate; NAAG, N-acetylaspartylglutamate; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation; V1, primary visual cortex; Motor learning; Force adaptation; Magnetic resonance spectroscopy; tDCS; GABA
21.  Sex, GABA, and Nicotine: The Impact of Smoking on Cortical GABA Levels Across the Menstrual Cycle as Measured with Proton Magnetic Resonance Spectroscopy 
Biological psychiatry  2005;57(1):44-48.
Background
Given that nicotine modulates amino acid neurotransmission, we sought to examine the impact of nicotine on cortical γ-aminobutyric acid (GABA) levels in male and female smokers.
Methods
Healthy nicotine-dependent men (n = 10) and women (n = 6) underwent proton magnetic resonance spectroscopy (1H-MRS) to measure occipital cortex GABA concentrations. A subset of the smoking men (n = 5) underwent 1H-MRS scans before and after 48 hours of smoking abstinence, whereas each of the women were scheduled to undergo pre- and postabstinence scans during the follicular and luteal phases of one menstrual cycle. Healthy nonsmoking men (n = 7) and women (n = 13) underwent 1H-MRS for comparison.
Results
Short-term abstinence had no significant effect on cortical GABA concentrations in either men or women. There was, however, a significant effect of sex, diagnosis (smoker/nonsmoker), and menstrual cycle phase on cortical GABA levels, such that female smokers experienced a significant reduction in cortical GABA levels during the follicular phase and no cyclicity in GABA levels across the menstrual cycle, whereas cortical GABA levels were similar in smoking and nonsmoking men.
Conclusions
Taken together with previous 1H-MRS data showing abnormalities in occipital cortex GABA concentrations in several affective disorders, our preliminary finding that nicotine modulation of GABA levels varies by sex provides a further rationale for investigating the impact of nicotine on central GABAergic function as a potential risk factor for women to experience depressive symptoms during smoking cessation.
doi:10.1016/j.biopsych.2004.09.021
PMCID: PMC4097033  PMID: 15607299
Nicotine; smoking; abstinence; menstrual cycle; GABA; sex
22.  Dorso-lateral prefrontal γ-amino butyric acid in men predicts individual differences in rash impulsivity 
Biological psychiatry  2011;70(9):866-872.
Background
Impulsivity is a multifaceted personality construct associated with numerous psychiatric disorders. Recent research has characterized four facets of impulsivity: ‘urgency’ (the tendency to act rashly especially in the context of distress or cravings); ‘lack of premeditation’ (not envisaging the consequences of actions); ‘lack of perseverance’ (not staying focused on a task); ‘sensation seeking’ (engaging in exciting activities). Urgency is particularly associated with clinical populations and problematic disinhibited behaviour.
Methods
We used magnetic resonance spectroscopy (MRS) to measure concentration of the inhibitory neurotransmitter γ-amino butyric acid (GABA) in the dorso-lateral prefrontal cortex (dlPFC) in two cohorts of 12 and 13 participants.
Results
We find that variation in trait urgency in healthy men correlates with GABA concentration in the dlPFC. The result was replicated in an independent cohort. More GABA predicted lower urgency scores, consistent with a role in self-control for GABA-mediated inhibitory mechanisms in dlPFC.
Conclusions
These findings help account for individual differences in self-control, and thus clarify the relationship between GABA and a wide range of psychiatric disorders associated with impaired self-control.
doi:10.1016/j.biopsych.2011.05.030
PMCID: PMC3192031  PMID: 21757187
Self-control; inhibition; urgency; GABRA2; externalizing; neurochemistry; personality; Stop-signal
23.  Insula and anterior cingulate GABA levels in post-traumatic stress disorder: Preliminary findings using magnetic resonance spectroscopy 
Depression and anxiety  2013;31(2):115-123.
Background
Increased reactivity of the insular cortex and decreased activity of the dorsal anterior cingulate (ACC) are seen in functional imaging studies of post-traumatic stress disorder (PTSD), and may partly explain the persistent fear- and anxiety-proneness that characterize the disorder. A possible neurochemical correlate is altered function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). We report results from what we believe is the first study applying proton magnetic resonance spectroscopy (1H-MRS) to measure brain GABA in PTSD.
Methods
Thirteen adults with DSM-IV PTSD and 13 matched healthy control subjects underwent single voxel 1H-MRS at 4 Tesla. GABA was measured in the right anterior insula and dorsal anterior cingulate, using MEGAPRESS spectral editing. Subjects were interviewed with the Structured Clinical Interview for DSM-IV and the Clinician Administered PTSD Scale, and also completed the State and Trait Anxiety Inventory.
Results
Insula GABA was significantly lower in PTSD subjects than in controls, and dorsal ACC GABA did not differ significantly between the groups. Insula GABA was not significantly associated with severity of PTSD symptoms. However, lower insula GABA was associated with significantly higher state and trait anxiety in the subject sample as a whole.
Conclusions
PTSD is associated with reduced GABA in the right anterior insula. This preliminary evidence of the 1H-MRS GABA metabolite as a possible biomarker of PTSD encourages replication in larger samples and examination of relations with symptom dimensions. Future studies also should examine whether insula GABA is a marker of anxiety proneness, cutting across clinical diagnostic categories.
doi:10.1002/da.22155
PMCID: PMC3894264  PMID: 23861191
post-traumatic stress disorder; magnetic resonance spectroscopy; anxiety; insular cortex; GABA
24.  Hippocampal extracellular GABA correlates with metabolism in human epilepsy 
Metabolic brain disease  2008;23(4):457-468.
As the major inhibitory neurotransmitter in human brain, GABA is an important modulator of hyperexcitability in epilepsy patients. Given the high energetic cost of neurotransmission and synaptic activity, GABA concentrations may be hypothesized to correlate with metabolic function. We studied human epilepsy patients undergoing intracranial EEG monitoring for seizure localization to examine microdialysis measures of extracellular GABA (ecGABA), pre-operative MR spectroscopic measures of neuronal mitochondrial function (NAA/Cr), and wherever possible, neuropathology and hippocampal volumetry. Two groups undergoing intracranial monitoring for seizure localization were studied: surgically treated hippocampal epilepsy (MTLE) and neocortical (non-hippocampal seizure onset) epilepsy. All data are hippocampal and thus these groups allow comparisons between the epileptogenic and non-epileptogenic regions. ecGABA was measured using in vivo microdialysis performed during intracranial monitoring. Pre-operative in vivo MR spectroscopic imaging was performed to measure the ratio of N-acetyl aspartate (NAA) to creatine. Standard methods for neuropathology and hippocampal volumetry were used. In the neocortical group, increased ecGABA correlated with greater NAA/Cr (R=+0.70, p<0.015, n=12) while in the MTLE group, increased ecGABA linked with decreased NAA/Cr (R=−0.94, p<0.001, n=8). In MTLE, ecGABA (increased) and NAA/Cr (decreased) correlated with increased glial cell numbers (R=+0.71, p<0.01, n=12, R=−0.76 p<0.03 respectively). No relationship was seen between ecGABA and hippocampal volumes in either group. In epilepsy, ecGABA increases occur across a range of metabolic function. Outside the seizure focus, ecGABA and NAA/Cr increase together; in contrast, within the seizure focus, ecGABA increases with declining mitochondrial function.
doi:10.1007/s11011-008-9106-5
PMCID: PMC3578212  PMID: 18807158
Epilepsy; GABA; NAA; Microdialysis; Hippocampus; Metabolism
25.  Polysubstance and Alcohol Dependence: Unique Abnormalities of Magnetic Resonance-Derived Brain Metabolite Levels 
Drug and alcohol dependence  2012;130(0):30-37.
BACKGROUND
Although comorbid substance misuse is common in alcohol dependence, and polysubstance abusers (PSU) represent the largest group of individuals seeking treatment for drug abuse today, we know little about potential brain abnormalities in this population. Brain magnetic resonance spectroscopy studies of mono-substance use disorders (e.g., alcohol or cocaine) reveal abnormal levels of cortical metabolites (reflecting neuronal integrity, cell membrane turnover/synthesis, cellular bioenergetics, gliosis) and altered concentrations of glutamate and γ-aminobutyric acid (GABA). The concurrent misuse of several substances may have unique and different effects on brain biology and function compared to any mono-substance misuse.
METHODS
High field brain magnetic resonance spectroscopy at 4 Tesla and neurocognitive testing were performed at one month of abstinence in 40 alcohol dependent individuals (ALC), 28 alcohol dependent PSU and 16 drug-free controls. Absolute metabolite concentrations were calculated in anterior cingulate (ACC), parieto-occipital (POC) and dorsolateral prefrontal cortices (DLPFC).
RESULTS
Compared to ALC, PSU demonstrated significant metabolic abnormalities in the DLPFC and strong trends to lower GABA in the ACC. Metabolite levels in ALC and light drinking controls were statistically equivalent. Within PSU, lower DLPFC GABA levels related to greater cocaine consumption. Several cortical metabolite concentrations were associated with cognitive performance.
CONCLUSIONS
While metabolite concentrations in ALC at one month of abstinence were largely normal, PSU showed persistent and functionally significant metabolic abnormalities, primarily in the DLPFC. Our results point to specific metabolic deficits as biomarkers in polysubstance misuse and as targets for pharmacological and behavioral PSU-specific treatment.
doi:10.1016/j.drugalcdep.2012.10.004
PMCID: PMC3624044  PMID: 23122599
Magnetic resonance spectroscopy; substance use comorbidity; alcohol dependence; brain metabolite concentrations; dorsolateral prefrontal cortex; neurocognition

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