Richard A.E. Edden

Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans

Functional imaging of the human brain is an increasingly important technique for clinical and cognitive neuroscience research, with functional MRI (fMRI) of the blood oxygen level-dependent (BOLD) response and electroencephalography or magnetoencephalography (MEG) recordings of neural oscillations being 2 of the most popular approaches. However, the neural and physiological mechanisms that generate these responses are only partially understood and sources of interparticipant variability in these measures are rarely investigated. Here, we test the hypothesis that the properties of these neuroimaging metrics are related to individual levels of cortical inhibition by combining magnetic resonance spectroscopy to quantify resting GABA concentration in the visual cortex, MEG to measure stimulus-induced visual gamma oscillations and fMRI to measure the BOLD response to a simple visual grating stimulus. Our results demonstrate that across individuals gamma oscillation frequency is positively correlated with resting GABA concentration in visual cortex (R = 0.68; P < 0.02), BOLD magnitude is inversely correlated with resting GABA (R = −0.64; P < 0.05) and that gamma oscillation frequency is strongly inversely correlated with the magnitude of the BOLD response (R = −0.88; P < 0.001). Our results are therefore supportive of recent theories suggesting that these functional neuroimaging metrics are dependent on the excitation/inhibition balance in an individuals cortex and have important implications for the interpretation of functional imaging results, particularly when making between-group comparisons in clinical research.

Orientation Discrimination Performance Is Predicted by GABA Concentration and Gamma Oscillation Frequency in Human Primary Visual Cortex

Neuronal orientation selectivity has been shown in animal models to require corticocortical network cooperation and to be dependent on the presence of GABAergic inhibition. However, it is not known whether variability in these fundamental neurophysiological parameters leads to variability in behavioral performance. Here, using a combination of magnetic resonance spectroscopy, magnetoencephalography, and visual psychophysics, we show that individual performance on a visual orientation discrimination task is correlated with both the resting concentration of GABA and the frequency of stimulus-induced gamma oscillations in human visual cortex. Behaviorally, a strong oblique effect was found, with the mean angular threshold for oblique discrimination being five times higher than that for vertically oriented stimuli. Similarly, we found an oblique effect for the dependency of performance on neurophysiological parameters. Orientation detection thresholds were significantly negatively correlated with visual cortex GABA concentration for obliquely oriented patterns (r = −0.65, p < 0.015) but did not reach significance for vertically oriented stimuli (r = −0.39, p = 0.2). Similarly, thresholds for obliquely oriented stimuli were negatively correlated with gamma oscillation frequency (r = −0.65, p < 0.017), but thresholds for vertical orientations were not (r = −0.02, p = 0.9). Gamma oscillation frequency was positively correlated with GABA concentration in primary visual cortex (r = 0.67, p < 0.013). These results confirm the importance of GABAergic inhibition in orientation selectivity and demonstrate, for the first time, that interindividual performance on a simple visual task is linked to neurotransmitter concentration. The results also suggest a key role for GABAergic gamma oscillations in visual discrimination tasks.

In vivo magnetic resonance spectroscopy of GABA: A methodological review

Magnetic resonance spectroscopy (MRS) is a powerful methodology that allows the direct detection of endogenous metabolites in the human body non-invasively in vivo. Although historically most often applied within a clinical context, there is increasing uptake (as there is with structural and functional MR imaging) of MRS to study the healthy brain. Although the principal inhibitory neurotransmitter in the human brain GABA, or γ-aminobutyric acid (H3N+CH2CH2CH2COO−), is only present in the human brain at millimolar levels, it is possible to measure GABA concentration with MRS, usually by tailoring the MRS experiment specifically to isolate GABA signals from the spectrum. This review will summarize the MRS methods proposed for detecting GABA, and address their various applications to date. Although the majority of cortical neurons are glutamatergic, approximately one sixth of cortical neurons are GABAergic inter-neurons [1]. There is wide interest within the clinical and basic neuroscience community in studying the role of inhibitory processes in normal brain function and the pathophysiology of disease. Both GABA receptors and transporters have been well characterized, and associated genes have been implicated by genetic studies of schizophrenia and bipolar disorder. Two main sub-types of GABA receptor, GABAA and GABAB, mediate the synaptic effects of GABA, and synaptic GABA is rapidly removed by high-affinity GABA transporters (GAT). GABA is produced from glutamate by glutamic acid decarboxylase (GAD) within GABAergic neurons and is metabolised to succinic acid semialdehyde by GABA transaminase (GABA-T) and thence to succinate, primarily within astrocytic mitochondria [2]. Among a wide variety of methods for studying GABA and GABAergic processes, the only technique that allows the direct, non-invasive detection of endogenous GABA in vivo in the brain is magnetic resonance spectroscopy (MRS). The purpose of this review is to introduce MRS methods that detect GABA in vivo, and to summarize the existing published literature applying these methods.

Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine- induced psychopathology

Preclinical studies suggest that ketamine-induced psychopathology is mediated, in part, by increased glutamate release, hypothesized to occur via inhibition of GABAergic interneurons. Using proton magnetic resonance spectroscopy (1H-MRS), we tested this hypothesis in healthy humans. Ketamine increased anterior cingulate cortex glutamate levels, which correlated with the degree of positive psychotic symptoms. Ketamine did not affect subcortical gamma-aminobutyric acid (GABA) levels.

Gannet: A batch‐processing tool for the quantitative analysis of gamma‐aminobutyric acid–edited MR spectroscopy spectra

The purpose of this study is to describe the Gannet toolkit for the quantitative batch analysis of gamma‐aminobutyric acid (GABA) ‐edited MRS data.

Nuclear Overhauser Enhancement (NOE) Imaging in the Human Brain at 7 T

Chemical exchange saturation transfer (CEST) is a magnetization transfer (MT) technique to indirectly detect pools of exchangeable protons through the water signal. CEST MRI has focused predominantly on signals from exchangeable protons downfield (higher frequency) from water in the CEST spectrum. Low power radiofrequency (RF) pulses can slowly saturate protons with minimal interference of conventional semi-solid based MT contrast (MTC). When doing so, saturation-transfer signals are revealed upfield from water, which is the frequency range of non-exchangeable aliphatic and olefinic protons. The visibility of such signals indicates the presence of a relayed transfer mechanism to the water signal, while their finite width reflects that these signals are likely due to mobile solutes. It is shown here in protein phantoms and the human brain that these signals build up slower than conventional CEST, at a rate typical for intramolecular nuclear Overhauser enhancement (NOE) effects in mobile macromolecules such as proteins/peptides and lipids. These NOE-based saturation transfer signals show a pH dependence, suggesting that this process is the inverse of the well-known exchange-relayed NOEs in high resolution NMR protein studies, thus a relayed-NOE CEST process. When studying 6 normal volunteers with a low-power pulsed CEST approach, the relayed-NOE CEST effect was about twice as large as the CEST effects downfield and larger in white matter than gray matter. This NOE contrast upfield from water provides a way to study mobile macromolecules in tissue. First data on a tumor patient show reduction in both relayed NOE and CEST amide proton signals leading to an increase in magnetization transfer ratio asymmetry, providing insight into previously reported amide proton transfer (APT) effects in tumors.

In vivo detection of GABA and glutamate with MEGA-PRESS: Reproducibility and gender effects

To evaluate the reproducibility of γ‐amino‐butyric acid (GABA) and glutamate concentrations derived using three different spectral fitting methods, and to investigate gender‐related differences in neurotransmitter levels.

Theoretical and experimental investigation of the VASO contrast mechanism

Vascular space occupancy (VASO)‐dependent functional MRI (fMRI) is a blood‐nulling technique capable of generating microvascular cerebral blood volume (CBV)‐weighted images. It is shown that at high magnetic field (3.0T) and high spatial resolution (1.89 × 1.89 × 3 mm3), the VASO signal changes are too large (6–7%) to originate from CBV effects alone. Additional contributions are investigated theoretically and experimentally as a function of MRI parameters (TR and TE), as well as the signal‐to‐noise ratio, (SNR) and spatial resolution. First, it is found that an arterial spin labeling (ASL) contribution causes large negative VASO signal changes at short TR. Second, even at high fMRI spatial resolution, CSF volume contributions (7–13%) cause VASO signal changes to become more negative, most noticeably at long TR and TE. Third, white matter (WM) effects reduce signal changes at lower spatial resolution. The VASO technique has been tested using different stimulus paradigms and field strengths ( 1–3 ), giving results consistent with comparable tasks investigated using BOLD and cerebral blood flow (CBF)‐based techniques. Finally, simulations show that a mixture of fresh and steady‐state blood may significantly alter signal changes at short TR (≤3 s), permitting larger VASO signal changes than expected under pure steady‐state conditions. Thus, many competing effects contribute to VASO contrast and care should be taken during interpretation. Magn Reson Med, 2006.

Spatial effects in the detection of γ-aminobutyric acid: Improved sensitivity at high fields using inner volume saturation

The MEGA‐PRESS‐IVS method has been developed, which combines MEGA (a frequency‐selective editing technique) editing with the point‐resolved spectroscopy sequence (PRESS) and inner volume saturation (IVS) localization, reducing the deleterious effects of spatial variation in coupling evolution. The IVS method has been previously described for improved efficiency of lactate detection. The current study demonstrates that the combination of MEGA‐PRESS with IVS results in increased sensitivity for edited single‐voxel measurements of glutamate and γ‐aminobutyric acid (GABA). A four‐compartment model of coupling evolution is investigated through simple product operators and full spin‐system simulations and the predicted pattern of signal evolution is demonstrated through MEGA‐PRESS‐MRSI. MEGA‐PRESS‐IVS is then compared to MEGA‐PRESS in a phantom and an average signal increase of 24% is demonstrated in five healthy volunteers. Magn Reson Med, 2007.

Individual Differences in Subconscious Motor Control Predicted by GABA Concentration in SMA

Subliminal visual stimuli affect motor planning, but the size of such effects differs greatly between individuals. Here, we investigated whether such variation may be related to neurochemical differences between people. Cortical responsiveness is expected to be lower under the influence of more of the main inhibitory neurotransmitter, GABA. Thus, we hypothesized that, if an individual has more GABA in the supplementary motor area (SMA)--a region previously associated with automatic motor control--this would result in smaller subliminal effects. We measured the reversed masked prime--or negative compatibility--effect, and found that it correlated strongly with GABA concentration, measured with magnetic resonance spectroscopy. This occurred specifically in the SMA region, and not in other regions from which spectroscopy measurements were taken. We replicated these results in an independent cohort: more GABA in the SMA region is reliably associated with smaller effect size. These findings suggest that, across individuals, the responsiveness of subconscious motor mechanisms is related to GABA concentration in the SMA.