In vivo quantification of intracerebral GABA by single-voxel 1H-MRS—How reproducible are the results?

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Abstract

Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the human brain. It plays a decisive role in a variety of nervous system disorders, such as anxiety disorders, epilepsy, schizophrenia, insomnia, and many others. The reproducibility of GABA quantification results obtained with a single-voxel spectroscopy J-difference editing sequence with Point Resolved Spectroscopy localization (MEGA-PRESS) was determined on a 3.0 Tesla MR scanner in healthy adults. Eleven volunteers were measured in long- and short-term intervals. Intra- and inter-subject reproducibility were evaluated. Internal referencing of GABA+ to total creatine (tCr) and water (H2O), as well as two different post-processing methods for the evaluation (signal integration and time-domain fitting) were compared. In all subjects lower coefficient of variation and therefore higher reproducibility can be observed for fitting compared to integration. The GABA+/tCr ratio performs better than the GABA+/H2O ratio or GABA+ without internal referencing for both fitting and integration (GABA+/tCr: 13.3% and 17.0%; GABA+/H2O: 15.0% and 17.8%; GABA+: 19.2% and 21.7%). Four-day measurements on three subjects showed higher intra- than inter-subject reproducibility (GABA+/tCr ∼10–12%). With a coefficient of variation of about 13% for inter-subject and 10–12% for intra-subject variability of GABA+/tCr, this technique seems to be a precise tool that can detect GABA confidently. The results of this study show the reproducibility limitations of GABA quantification in vivo, which are necessary for further clinical studies.

Introduction

Gamma aminobutyric acid (GABA) is the chief inhibitory neurotransmitter in the central nervous system and plays a decisive role in a variety of nervous system disorders, such as anxiety disorders, epilepsy, schizophrenia, insomnia and many others [1].

To better understand the mechanisms of diseases like epilepsy, or to monitor medical treatment that affects GABA metabolism such as antiepileptic therapy, non-invasive techniques for detection of intracerebral GABA such as proton MR spectroscopy (1H-MRS) are of great importance. However, quantifying intracerebral GABA by 1H-MRS is not straightforward, as resonances of GABA overlap with signals of other metabolites such as glutamate (Glu), N-acetylaspartate (NAA), total creatine (tCr) and macromolecules (MM). In addition, the concentration and subsequently the signal-to-noise ratio (SNR) of GABA in cortical grey matter is low (∼1 mM in vivo) compared to commonly quantified metabolites [2], [3]. Both make reliable quantification of GABA difficult.

Therefore, quantification requires sophisticated editing sequences, which have been the topic of many studies [2], [4], [5], [6], [7], [8]. These sequences can be divided into the following groups: (1) J-difference editing methods that cancel the tCr signal at 3.03 ppm by taking advantage of the J-coupling between the GABA-3 and GABA-4 resonance [6]; (2) multiple quantum filtering methods that suppress overlapping signals of GABA-3/4 [7]; and (3) two-dimensional spectroscopy methods to separate GABA-3/4 from overlapping signals in the second spectral dimension [5]. Due to the conceptual simplicity and the ease of implementation, J-difference editing using Point Resolved Spectroscopy with MEGA suppression (MEGA-PRESS) [6] has evolved the most commonly used method.

Different ways of quantification have been employed in the past [2], [9]. Either internal referencing to tCr or external referencing to phantom solutions was applied. Advantages and disadvantages of different referencing methods have been discussed previously [10]. While external referencing may be prone to system instability, it is known that tCr that is frequently used for internal referencing may not be stable for comparisons between patients and healthy controls, as reported previously in many disorders [11], [12].

The aims of this study were fourfold: first, to determine the in vivo reproducibility of GABA quantification by a MEGA-PRESS editing sequence, comparable to the one used by Kaiser et al. [4]; second, to compare reproducibility for external referencing, and internal reference to water (H2O) and to tCr; third, to evaluate the inter- and intra-subject variability and scan–rescan reproducibility; and fourth, to compare two post-processing tools for quantification of signals. The first quantification method is based on integration using MestreC [13] spectroscopy processing software. The second method is time-domain fitting (AMARES) [14].

Section snippets

Subjects

Eleven healthy volunteers (age 30.0 ± 7.1 years, five male, six female) were included in this study. The study complied with the Declaration of Helsinki and was approved by our Institutional Review Board. Written, informed consent was obtained from all subjects. None of the healthy volunteers demonstrated pathological findings on MR imaging or had any known history of neurological or psychiatric disorders. All subjects were light drinkers (1–14.9 g/day ethanol), non-smokers or light smokers (<20

Results

The quantification of GABA was performed for 87 voxels in 11 subjects. Fig. 4 illustrates representative in vivo spectra in comparison to acquired phantom data (Fig. 3). The triplet structure of GABA is clearly visible in the unsuppressed phantom spectrum. In contrast a pseudo-doublet can be observed in the edited spectrum after subtraction. This doublet can be also resolved in vivo (Fig. 4). All results are shown in ratios to an internal reference and not in absolute values. However, this does

Discussion

In the present study, the intra- and inter-subject reproducibility of GABA quantification results employing a MEGA suppression method combined with different post-processing procedures and referencing methods was investigated. We compared internal reference to water and tCr, as well as quantification by time-domain fitting in contrast to signal integration. This knowledge is important for non-invasive determination of intracerebral GABA in many psychiatric and neurological diseases [1], [15],

Conclusion

The results of our study show that in vivo1H-MRS of intracerebral GABA can be a fast, and reproducible method on higher field (3.0 T) clinical routine scanners, if proper post-processing and internal referencing are employed. This method has the potential to be used in clinical and scientific settings to detect even small alterations in intracerebral GABA.

Conflict of interest statement

None declared.

Acknowledgments

This study was supported by ELAN (Fonds für Forschung und Lehre am Universitätsklinikum Erlangen), Wilhelm Sander Foundation and Österreichische Forschungsförderungsgesellschaft (FFG) mbH (Grant #812104).

Cited by (0)

Parts of this study were presented at: Bogner, W., et al., Quantification of intercerebral GABA by 1H-MRS—How reproducible are the results? (scientific paper). ECR, 2008. Vienna, Control number: 5763 (B-429); Bogner, W., et al., Strategies for reliable quantification of intracerebral GABA by 1H-MRS (electronic poster). ISMRM, 2008. Toronto, ID# 4955.

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