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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.

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.

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.

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.

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.

Summary

Subliminal visual stimuli affect motor planning [1] but the size of such effects differs greatly between individuals [2, 3]. 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 [4]. Thus we hypothesized that if an individual has more GABA in the supplementary motor area (SMA) – a region previously associated with automatic motor control [5] – 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.

Background

Panic disorder (PD) is hypothesized to be associated with altered function of the major inhibitory neurotransmitter, gamma-amino butyric acid (GABA). Previous proton magnetic resonance spectroscopy (MRS) studies found lower GABA concentrations in the occipital cortex of subjects with PD relative to healthy controls. The current study is the first MRS study to compare GABA concentrations between unmedicated PD subjects and controls in the prefrontal cortex (PFC).

Methods

Unmedicated subjects with PD (n=17) and age- and sex-matched healthy controls (n=17) were scanned on a 3 Tesla scanner using a transmit-receive head coil that provided a sufficiently homogenous radiofrequency field to obtain spectroscopic measurements in the dorsomedial/dorsal anterolateral and ventromedial areas of the PFC.

Results

The prefrontal cortical GABA concentrations did not differ significantly between PD subjects and controls. There also was no statistically significant difference in Glx, choline or N-acetyl-aspartate concentrations.

Conclusions

The previously reported finding of reduced GABA concentrations in the occipital cortex of PD subjects does not appear to extend to the PFC.

Objective

Impaired function of the central gamma-aminobutyric acid (GABA) system, which provides the brain’s major inhibitory pathways, is thought to play an important role in the pathophysiology of anxiety disorders. The effect of acute psychological stress on the human GABA-ergic system is still unknown, however. The purpose of this study was to determine the effect of acute stress on prefrontal GABA levels.

Method

A recently developed noninvasive magnetic resonance spectroscopy method was used to measure changes in the GABA concentration of the prefrontal cortex in 10 healthy human subjects during a threat-of-shock condition and during a safe condition (two sessions on different days). The main outcome measure was the mean GABA concentration within a 3×3×2-cm3 voxel selected from the medial prefrontal cortex.

Results

Prefrontal GABA decreased by approximately 18% in the threat-of-shock condition relative to the safe condition. This reduction was specific to GABA, since the concentrations of N-acetyl-aspartate, choline-containing compounds, and glutamate/glutamine levels obtained in the same spectra did not change significantly.

Conclusions

This result appeared compatible with evidence from preclinical studies in rodents, which showed rapid presynaptic down-regulation of GABA-ergic neurotransmission in response to acute psychological stress. The molecular mechanism and functional significance of this reduced inhibitory effect of acute psychological stress in relation to impaired GABA-ergic function in anxiety disorders merit further investigation.

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.

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.

γ-amino-butyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyl-transferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy (MRS). Two of the GAD1 SNPs (rs1978340 [p=0.005] and rs769390 [p=0.004]) showed effects on GABA levels as did COMT val158met (p=0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313 and rs769390) for interaction with COMT val158met based on prior clinical results. In this model, rs11542313 and COMT val158met showed significant main effects (p=0.001 and 0.003, respectively) and a trend towards a significant interaction (p=0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background (N=6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.

γ-Aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyltransferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy. Two of the GAD1 SNPs (rs1978340 (p=0.005) and rs769390 (p=0.004)) showed effects on GABA levels as did COMT val158met (p=0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313, and rs769390) for interaction with COMT val158met based on previous clinical results. In this model, rs11542313 and COMT val158met showed significant main effects (p=0.001 and 0.003, respectively) and a trend toward a significant interaction (p=0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background (N=6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.

Continuous theta burst stimulation (cTBS) is a novel transcranial stimulation technique that causes significant inhibition of synaptic transmission for ≤1 h when applied over the primary motor cortex (M1) in humans. Here we use magnetic resonance spectroscopy to define mechanisms mediating this inhibition by noninvasively measuring local changes in the cortical concentrations of γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx). cTBS to the left M1 led to an increase in GABA compared with stimulation at a control site without significant change in Glx. This direct evidence for increased GABAergic interneuronal activity is framed in terms of a new hypothesis regarding mechanisms underlying cTBS.

Fetal striatal cell suspensions were grafted stereotaxically into the infarcted striatum of rats, and reconstruction of striatopallidal GABA transmission and behavior were investigated. Occlusion of the middle cerebral artery (MCA) for one hour induced ischemic infarcts mainly in the lateral striatum, as detected by magnetic resonance imaging (MRI) and histology. Ischemic rats had deficits in the performance of a passive avoidance task, both acquisition and retention, but no changes in general circadian actograms. In these animals pallidal GABA, detected by microdialysis, decreased to about half of control levels. There were suggestions of an improvement in passive avoidance performance in the grafted animals. Pallidal GABA concentrations recovered almost to control levels, and were increased by infusions of the GABA uptake blocker nipecotic acid. These data indicate that neural transplantation is a promising approach to improve the deficits in chemical transmission and behavior following ischemic infarcts in rat striatum.

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in human brain and has been implicated in several neuropsychiatric disorders. In-vivo human brain GABA concentrations are near the detection limit for magnetic resonance spectroscopy (∼1 mM) and because of overlap with more abundant compounds, spectral editing is generally necessary to detect GABA. In previous reports, GABA spectra edited by J-difference spectroscopy vary considerably in appearance. We have evaluated the factors that affect GABA spectra and the conditions necessary for robust acquisition of J-difference spectra from arbitrary brain regions. In particular, we demonstrate that variations in spectral quality can be explained in part by the incoherent addition of transients that results from shot to shot frequency and phase variations. An automated time-domain spectral alignment strategy is presented that enables reproducible acquisition of high-quality GABA spectra at 3 Tesla with a standard 30 cm T/R volume coil. Representative GABA spectra from human frontal lobe, an area where susceptibility-induced frequency and phase variations are especially troublesome, are presented that demonstrate the robustness of the acquisition and data handling strategy used in this study.

Background

Despite widely-replicated abnormalities of gamma-aminobutyric acid (GABA) neurons in schizophrenia postmortem, few studies have measured tissue GABA levels in vivo. We used proton magnetic resonance spectroscopy to measure tissue GABA levels in participants with schizophrenia and healthy controls in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC).

Methods

21 schizophrenia participants effectively treated on a stable medication regimen (mean age 39.0, 14 male) and 19 healthy controls (mean age 36.3, 12 male) underwent a proton magnetic resonance spectroscopy scan using GABA-selective editing at 4 Tesla after providing informed consent. Data were collected from two 16.7cc voxels and analyzed using LCModel.

Results

We found elevations in GABA/Cr in the schizophrenia group compared with controls (F(1,65)=4.149, p=0.046) in both brain areas (15.5% elevation in ACC, 11.9% in POC). We also found a positive correlation between GABA/Cr and Glu/Cr which was not accounted for by %GM or brain region.

Conclusions

We found elevated GABA/Cr in participants with chronically treated schizophrenia. Postmortem studies report evidence for dysfunctional GABAergic neurotransmission in schizophrenia. Elevated GABA levels, whether primary to illness or compensatory to another process, may be associated with dysfunctional GABAergic neurotransmission in chronic schizophrenia.

Background

Significant alterations in γ-aminobutyric acid (GABA) and glutamate levels have been previously reported in symptomatic and remitted major depressive disorder (MDD); however, no studies to date have investigated potential associations between these amino acid neurotransmitters and treatment-resistance.

Methods

The objective of this study was to compare occipital cortex (OCC) and anterior cingulate cortex (ACC) GABA and glutamate+glutamine (“Glx”) levels measured in vivo by proton magnetic resonance spectroscopy (1H MRS) in 15 medication-free treatment-resistant depression (TRD) patients with those in 18 non-treatment-resistant MDD (nTRD) patients and 24 healthy volunteers (HVs).

Results

Levels of OCC GABA relative to voxel tissue water (W) were decreased in TRD patients compared to both HV (20.2% mean reduction; p=.001; Cohen’s d=1.3) and nTRD subjects (16.4% mean reduction; p=.007; Cohen’s d=1.4). There was a similar main effect of diagnosis for ACC GABA/W levels (p=.047; Cohen’s d=0.76) with TRD patients exhibiting reduced GABA in comparison to the other two groups (22.4–24.5% mean reductions). Group differences in Glx/W were not significant in either brain region in primary ANOVA analyses. Only GABA results in OCC survived correction for multiple comparisons.

Conclusions

Our findings corroborate previous reports of decreased GABA in MDD and provide initial evidence for a distinct neuronal amino acid profile in patients who have failed to respond to several standard antidepressants, possibly indicative of abnormal glutamate/glutamine/GABA cycling. Given interest in novel antidepressant mechanisms in TRD that selectively target amino acid neurotransmitter function, the translational relevance of these findings awaits further study.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain. Understanding the GABA concentration, in vivo, is important to understand normal brain function. Using MEGA point resolved spectroscopy (MEGA-PRESS) sequence with interleaved water scans to detect subject motion, GABA level of sensorimotor cortex was measured using a voxel was identified from a functional MRI scan. The GABA level in a 20 × 20 × 20 mm3 voxel consisting of 37 ± 7% GM, 52 ± 12% WM, and 11 ± 8% CSF in the sensorimotor region was measured to be 1.43 ± 0.48 mM. In addition, using linear regression analysis, GABA concentrations within gray and white matter were calculated to be 2.87 ± 0.61 and 0.33 ± 0.11 mM, respectively.

Control of heart rate variability (HRV) via modulation of sympathovagal balance is a key function of nucleus tractus solitarii (nTS) and dorsal motor nucleus of the vagus localized in the dorsomedial medulla oblongata. Normal blood pressure regulation involves precise balance of glutamate-glutamine-GABA (Glu-Gln-GABA) transmitter systems, and angiotensin (Ang) II modulates these transmitters to produce tonic suppression of reflex function. It is not known, however, whether other brain transmitters/metabolites are indicators of baroreflex function. This study establishes the concept that comprehensive baseline transmitter/metabolite profiles obtained using in vivo 1H Magnetic Resonance Spectroscopy (1H MRS) in rats with well characterized differences in resting blood pressure and baroreflex function can be used as indices of autonomic balance or baroreflex sensitivity. Glu concentration in dorsal medulla is significantly higher in ASrAogen rats compared to either SD and (mRen2)27. Glu levels and the ratio of Glu/Gln correlated positively with indices of higher vagal tone consistent with the importance of these neurotransmitters in baroreflex function. Interestingly, the levels of choline containing metabolites showed a significant positive correlation with spontaneous baroreflex sensitivity and a negative correlation with sympathetic tone. Thus, we demonstrate the concept that non-invasive assessment of neurochemical biomarkers may be used as an index of baroreflex sensitivity.

Background

Ethanol modulates glutamate and GABA function. However, little is known about the acute pharmacologic effects of ethanol on levels of GABA, glutamate, and other metabolites measurable in the human cortex in vivo using 1H magnetic resonance spectroscopy (MRS).

Methods

Eleven healthy social drinkers received two intravenous ethanol infusions that raised breath alcohol levels to a clamped plateau of 60 mg/dL over 60–70 minutes. The first infusion established tolerability of the procedure, and the second procedure, conducted 15±12 days later, was performed during 1H MRS of occipital GABA, glutamate, and other metabolites.

Results

The time course of brain ethanol approximated that of breath ethanol, but venous ethanol lagged by about 7 minutes. GABA fell 13±8% after 5 minutes of the ethanol infusion and remained reduced (p=0.003) throughout the measurement. The combination of N-acetylaspartate and N-acetylaspartyl glutamate (summed as NAA) fell steadily during the infusion by 8±3% (p=0.0036).

Conclusions

Ethanol reduced cortical GABA and NAA levels in humans. Reductions in GABA levels are consistent with facilitation of GABAA receptor function by ethanol. The gradual decline in NAA levels suggests inhibition of neural or metabolic activity in the brain.

Previous in vivo magnetic resonance spectroscopy (MRS) studies of gamma-aminobutyric acid (GABA) synthesis have relied on 13C label incorporation into GABA C2 from [1-13C] or [1,6-13C2]glucose. In this study, the [13C]GABA C1 signal at 182.3 ppm in the carboxylic/amide spectral region of localized in vivo 13C spectra was detected. GABA-transaminase of rat brain was inhibited by administration of gabaculine after pre-labeling of GABA C1 and its metabolic precursors with exogenous [2,5-13C2]glucose. A subsequent isotope chase experiment was performed by infusing unlabeled glucose, which revealed a markedly slow change in the labeling of GABA C1 accompanying the blockade of the GABA shunt. This slow labeling of GABA at elevated GABA concentration was attributed to the relatively small intercompartmental GABA-glutamine cycling flux that constitutes the main route of 13C label loss during the isotope chase. Because this study showed that using low RF power broadband stochastic proton decoupling is feasible at very high field strength, it has important implications for the development of carboxylic/amide 13C MRS methods to study brain metabolism and neurotransmission in human subjects at high magnetic fields.

As one of the most widespread drugs of abuse, nicotine has long been known to impact the brain, particularly with respect to addiction. However, the regional effects of nicotine on the concentrations and kinetics of amino acid neurotransmitters and some energetically related neurochemicals have been little studied. In this investigation, acute effects of nicotine were measured by 1H-observed/13C-edited nuclear magnetic resonance spectroscopy method in extracts obtained from nicotine-naïve, freely moving rats given 0.7 mg/kg nicotine or saline, with [1-13C] glucose to track metabolism. Nicotine was observed to exert significant effects on the concentrations of N-acetylaspartate (NAA), and γ-aminobutyric acid (GABA), particularly in the striatum. Nicotine decreased brain glucose oxidation, glutamate-glutamine neurotransmitter cycling, and GABA synthesis regionally, including in the parietal and occipital cortices and the striatum. The olfactory bulb showed kinetics that differed markedly from those observed in the rest of the brain. Independently of nicotine, the concentration of glutamate was found to be correlated significantly with levels of NAA and GABA, suggesting a potential interplay of energetics and excitatory and inhibitory neurotransmission. In summary, the study revealed that the neurochemicals were most affected in the cortex and striatum of the rat brain after acute nicotine treatment.

Summary

GABA modification plays an important role in motor cortical plasticity [1–4]. We therefore hypothesized that interindividual variation in the responsiveness of the GABA system to modification influences learning capacity in healthy adults. We assessed GABA responsiveness by transcranial direct current stimulation (tDCS), an intervention known to decrease GABA [5, 6]. The magnitude of M1 GABA decrease induced by anodal tDCS correlated positively with both the degree of motor learning and the degree of fMRI signal change within the left M1 during learning. This study therefore suggests that the responsiveness of the GABAergic system to modification may be relevant to short-term motor learning behavior and learning-related brain activity.

Highlights

► Change in GABA due to transcranial stimulation correlates with motor learning behavior ► GABA change also correlates with localized fMRI responses during short-term learning ► No correlations are found for these measures with GABA levels in visual cortex

Functional neuroimaging metrics are thought to reflect changes in neurotransmitter flux, but changes in neurotransmitter levels have not been demonstrated in humans during a cognitive task, and the relationship between neurotransmitter dynamics and hemodynamic activity during cognition has not yet been established. We evaluate the concentration of the major inhibitory (GABA) and excitatory (glutamate + glutamine: Glx) neurotransmitters and the cerebral perfusion at rest and during a prolonged delayed match-to-sample working memory task. Resting GABA levels in the dorsolateral prefrontal cortex correlated positively with the resting perfusion and inversely with the change in perfusion during the task. Further, only GABA increased significantly during the first working memory run and then decreased continuously across subsequent task runs. The decrease of GABA over time was paralleled by a trend towards decreased reaction times and higher task accuracy. These results demonstrate a link between neurotransmitter dynamics and hemodynamic activity during working memory, indicating that functional neuroimaging metrics depend on the balance of excitation and inhibition required for cognitive processing.

Background

Deficiency of 4-aminobutyrate aminotransferase (GABA-T) is a rare disorder of GABA catabolism, with only a single sibship reported. We report on a third case, a Japanese female infant with severe psychomotor retardation and recurrent episodic lethargy with intractable seizures, with the diagnosis facilitated by proton magnetic resonance (MR) spectroscopy (1H-MRS).

Methods

Neuroimaging was performed at the first episode of lethargy. For 1H-MRS, locations were placed in the semioval center and the basal ganglia. Quantification of metabolite concentrations were derived using the LCModel. We confirmed the diagnosis subsequently by enzyme and molecular studies, which involved direct DNA sequence analysis and the development of a novel multiplex ligation-dependent probe amplification test.

Results

1H-MRS analysis revealed an elevated GABA concentration in the basal ganglia (2.9 mmol/l). Based on the results of quantitative 1H-MRS and clinical findings, GABA-T deficiency was suspected and confirmed in cultured lymphoblasts. Molecular studies of the GABA-T gene revealed compound heterozygosity for a deletion of one exon and a missense mutation, 275G>A, which was not detected in 210 control chromosomes.

Conclusions

Our results suggest that excessive prenatal GABA exposure in the central nervous system (CNS) was responsible for the clinical manifestations of GABA transaminase deficiency. Our findings suggest the dual nature of GABA as an excitatory molecule early in life, followed by a functional switch to an inhibitory species later in development. Furthermore, quantitative 1H-MRS appears to be a useful, noninvasive tool for detecting inborn errors of GABA metabolism in the CNS.