Jamie Near

Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex

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.

Baseline GABA concentration and fMRI response

Coordination between glutamatergic excitatory neurons and gamma-aminobutyric acid (GABA)-ergic inhibitory interneurons is fundamental to the regulation of neuronal firing rates and is believed to have relevance to functional magnetic resonance imaging (fMRI) contrast. While much is known regarding the molecular behavior of excitatory and inhibitory processes, comparatively less is known regarding the role of such processes in explaining variations in fMRI and related hemodynamic imaging metrics. The relationship between baseline GABA levels, as measured by MR spectroscopy, and hemodynamic contrasts from four sequences in human visual cortex are investigated (n=12; field strength=3.0 T): blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF)-weighted arterial spin labelling (ASL), cerebral blood volume (CBV)-weighted vascular-space-occupancy (VASO), and arterial CBV (aCBV)-weighted inflow VASO (iVASO). Results indicate that baseline GABA levels (GABA+ macromolecules normalized to creatine) inversely correlate with BOLD reactivity (R=-0.70; P=0.01) and magnitude CBV-weighted VASO reactivity (R=-0.71; P=0.01). A trend for significance was found between baseline aCBV-weighted iVASO (R=-0.50; P=0.10) and baseline GABA. A positive correlation was found between baseline CBF-weighted ASL signal and GABA (R=0.65; P=0.02) and ASL time-to-peak and baseline GABA (R=0.58; P=0.05). These findings demonstrate that both the dominant BOLD fMRI contrast, as well as other emerging MR hemodynamic contrasts, have signal variations that are linked to baseline GABA levels.

A mechanism for value-guided choice based on the excitation-inhibition balance in prefrontal cortex.

Although the ventromedial prefrontal cortex (vmPFC) has long been implicated in reward-guided decision making, its exact role in this process has remained an unresolved issue. Here we show that, in accordance with models of decision making, vmPFC concentrations of GABA and glutamate in human volunteers predict both behavioral performance and the dynamics of a neural value comparison signal. These data provide evidence for a neural competition mechanism in vmPFC that supports value-guided choice.

Frequency and phase drift correction of magnetic resonance spectroscopy data by spectral registration in the time domain.

Frequency and phase drifts are a common problem in the acquisition of in vivo magnetic resonance spectroscopy (MRS) data. If not accounted for, frequency and phase drifts will result in artifactual broadening of spectral peaks, distortion of spectral lineshapes, and a reduction in signal‐to‐noise ratio (SNR). We present herein a new method for estimating and correcting frequency and phase drifts in in vivo MRS data.

Efficient γ-aminobutyric acid editing at 3T without macromolecule contamination: MEGA-SPECIAL.

One of the most commonly used methods for in vivo MRS detection of γ‐aminobutyric acid (GABA) is the MEGA‐point‐resolved spectroscopy (MEGA‐PRESS) technique. However, accurate quantification of GABA using MEGA‐PRESS is complicated by spectral co‐editing of macromolecular resonances. In this article, a new pulse sequence is presented which enables GABA editing at 3T with the removal of macromolecule contamination. This sequence combines the conventional MEGA editing scheme with the SPECIAL localisation technique, and is therefore named MEGA‐SPECIAL. Simulations and phantom experiments indicate that this new approach provides improved GABA editing efficiency relative to MEGA‐PRESS, and in vivo results demonstrate effective removal of macromolecule contamination. In a study of the occipital lobe of five healthy volunteers, the macromolecule‐corrected GABA/creatine ratio was found to be 0.093 ± 0.007 (mean ± standard deviation), whereas prior to macromolecule correction, the ratio was found to be 0.173 ± 0.013. Copyright

Local GABA concentration is related to network-level resting functional connectivity

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

Resting GABA and glutamate concentrations do not predict visual gamma frequency or amplitude

Significance In vitro and modeling studies have indicated that GABAergic signaling underlies gamma oscillations. It would be valuable to measure this correlation between GABA and gamma oscillations in the human brain, and a recent study [Muthukumaraswamy SD, et al. (2009) Proc Natl Acad Sci USA 106(20):8356–8361] indicated that this is possible, using magnetoencephalography and magnetic resonance spectroscopy. If true, such a correlation would make the gamma peak frequency a useful surrogate marker of cortical excitability for studies investigating clinical populations and/or the effects of pharmacological agents. However, magnetic resonance spectroscopy does not measure synaptic GABA specifically, and the results from the current study (n = 50) indicate that GABA, as measured with magnetic resonance spectroscopy, does not correlate with gamma peak frequency. Gamma band oscillations arise in neuronal networks of interconnected GABAergic interneurons and excitatory pyramidal cells. A previous study found a correlation between visual gamma peak frequency, as measured with magnetoencephalography, and resting GABA levels, as measured with magnetic resonance spectroscopy (MRS), in 12 healthy volunteers. If true, this would allow studies in clinical populations testing modulation of this relationship, but this finding has not been replicated. We addressed this important question by measuring gamma oscillations and GABA, as well as glutamate, in 50 healthy volunteers. Visual gamma activity was evoked using an established gratings paradigm, and we applied a beamformer spatial filtering technique to extract source-reconstructed gamma peak frequency and amplitude from the occipital lobe. We determined gamma peak frequency and amplitude from the location with maximal activation and from the location of the MRS voxel to assess the relationship of GABA with gamma. Gamma peak frequency was estimated from the highest value of the raw spectra and by a Gaussian fit to the spectra. MRS data were acquired from occipital cortex. We did not replicate the previously found correlation between gamma peak frequency and GABA concentration. Calculation of a Bayes factor provided strong evidence in favor of the null hypothesis. We also did not find a correlation between gamma activity and glutamate or between gamma and the ratio of GABA/glutamate. Our results suggest that cortical gamma oscillations do not have a consistent, demonstrable relationship to excitatory/inhibitory network activity as proxied by MRS measurements of GABA and glutamate.

Unedited in vivo detection and quantification of γ-aminobutyric acid in the occipital cortex using short-TE MRS at 3 T.

Short‐TE MRS has been proposed recently as a method for the in vivo detection and quantification of γ‐aminobutyric acid (GABA) in the human brain at 3 T. In this study, we investigated the accuracy and reproducibility of short‐TE MRS measurements of GABA at 3 T using both simulations and experiments. LCModel analysis was performed on a large number of simulated spectra with known metabolite input concentrations. Simulated spectra were generated using a range of spectral linewidths and signal‐to‐noise ratios to investigate the effect of varying experimental conditions, and analyses were performed using two different baseline models to investigate the effect of an inaccurate baseline model on GABA quantification. The results of these analyses indicated that, under experimental conditions corresponding to those typically observed in the occipital cortex, GABA concentration estimates are reproducible (mean reproducibility error, <20%), even when an incorrect baseline model is used. However, simulations indicate that the accuracy of GABA concentration estimates depends strongly on the experimental conditions (linewidth and signal‐to‐noise ratio). In addition to simulations, in vivo GABA measurements were performed using both spectral editing and short‐TE MRS in the occipital cortex of 14 healthy volunteers. Short‐TE MRS measurements of GABA exhibited a significant positive correlation with edited GABA measurements (R = 0.58, p < 0.05), suggesting that short‐TE measurements of GABA correspond well with measurements made using spectral editing techniques. Finally, within‐session reproducibility was assessed in the same 14 subjects using four consecutive short‐TE GABA measurements in the occipital cortex. Across all subjects, the average coefficient of variation of these four GABA measurements was 8.7 ± 4.9%. This study demonstrates that, under some experimental conditions, short‐TE MRS can be employed for the reproducible detection of GABA at 3 T, but that the technique should be used with caution, as the results are dependent on the experimental conditions. Copyright

Impact of frequency drift on gamma-aminobutyric acid-edited MR spectroscopy

To investigate the quantitative impact of frequency drift on Gamma‐Aminobutyric acid (GABA+)‐edited MRS of the human brain at 3 Tesla (T).

Modulation of GABA and resting state functional connectivity by transcranial direct current stimulation

We previously demonstrated that network level functional connectivity in the human brain could be related to levels of inhibition in a major network node at baseline (Stagg et al., 2014). In this study, we build upon this finding to directly investigate the effects of perturbing M1 GABA and resting state functional connectivity using transcranial direct current stimulation (tDCS), a neuromodulatory approach that has previously been demonstrated to modulate both metrics. FMRI data and GABA levels, as assessed by Magnetic Resonance Spectroscopy, were measured before and after 20 min of 1 mA anodal or sham tDCS. In line with previous studies, baseline GABA levels were negatively correlated with the strength of functional connectivity within the resting motor network. However, although we confirm the previously reported findings that anodal tDCS reduces GABA concentration and increases functional connectivity in the stimulated motor cortex; these changes are not correlated, suggesting they may be driven by distinct underlying mechanisms. DOI: http://dx.doi.org/10.7554/eLife.08789.001