Brain GABA editing by localized in vivo¹H magnetic resonance spectroscopy

Abstract

Editing of GABA by (1)H MRS in a specific brain area is a unique tool for in vivo non-invasive investigation of neurotransmission disorders. Selective GABA detection is achieved using sequences based on double quantum coherence (DQC). Our pulse sequence makes accurate measurements without artefacts due to spatial localization. The sequence was tested on a phantom solution. The effect of vigabatrin, a specific inhibitor of GABA transaminase, was measured in rat brain and GABA detection was performed in vivo in monkey brain using this procedure. Rats were split into two groups. In the control group, the rats had access to water and, in the other group (vigabatrin, VGB, rats), animals were allowed free access to drinking water containing vigabatrin. After 3 weeks of treatment, rats were anesthetized for in vivo NMR spectroscopy investigation. At the end of the experiment, brains were quickly removed, freeze-clamped and extracted with 4% perchloric acid. One part of the acid extract was used for GABA concentrations assessment by ion exchange chromatography with ninhydrin detection. The second was used for high-resolution NMR analysis. By chromatography measurements, the GABA concentration was 1.23+/-0.06 micromol/g for controls, while for vigabatrin-treated rats the GABA concentration was 4.89+/-1.60 micromol/g. The NMR in vivo results were closely correlated with the NMR ex vivo (r=0.99, p<0.01) and chromatography results (r=0.98, p<0.01). The correlation between ex vivo results and chromatography results was also high (r=0.99, p<0.001). This pulse sequence performed GABA editing from a 376 microl voxel located on the right basal ganglia area in a non-human primate brain. This in vivo GABA editing scheme can thus be proposed for accurate measurement of brain GABA concentrations.

The neurochemical profile quantified by in vivo 1H NMR spectroscopy

“…Although GABA concentrations remain stable throughout development (Kulak et al, 2010;Tkáč et al, 2003), modifications in metabolic and signaling fates of GABA occur at the time of GABAergic inhibitory synapse formation (Anderson et al, 1995) and with the increment of cortical GABA binding sites (Skerritt and Johnston, 1982). At low magnetic fields, GABA is difficult to measure in 1 H NMR spectra and its detection has been achieved by editing techniques, which are not exempt of quantification errors (Bielicki et al, 2004;Choi et al, 2005;Mescher et al, 1998;Terpstra et al, 2002). Higher magnetic fields, on the other hand, provide increased spectral resolution making GABA quantifiable (Deelchand et al, 2010;Gambarota et al, 2009;Mekle et al, 2009;Oz et al, 2006).…”

The Impact of Gabapentin Administration on Brain GABA and Glutamate Concentrations: A 7T 1H-MRS Study

“…All subjects gave written informed consent for participation in this study protocol, which was approved by the institutional review board at the Perelman School of Medicine of the University of Pennsylvania. A subset of the subjects (n ¼ 6) who completed the gabapentin administration also participated in a study of the reproducibility of the MEGA-PRESS GABA-editing sequence (Bielicki et al, 2004;Mescher et al, 1998). Ten subjects in total were scanned twice in the same day without drug administration, 13 were scanned twice 2 weeks apart.…”

“…GABA-edited single voxel spectra (SVS) were obtained with a custom-modified Point-RESolved Spectroscopy (PRESS) sequence with MEGA-PRESS GABA-editing pulses (Bielicki et al, 2004;Mescher et al, 1998) that are frequency selective either at 1.9 p.p.m. to the GABA -CH 2 protons attached to C2 (edit 'on') or at 7.5 p.p.m.…”

Prefrontal GABA levels in cocaine-dependent subjects increase with pramipexole and venlafaxine treatment

“…Although 1 H MRS does not differentiate between intracellular and extracellular GABA pools, GABA levels measured by 1 H MRS and chromatography are highly correlated (Bielicki et al 2004). 1 H MRS has documented that brain GABA levels are decreased in cocaine-dependent patients (Ke et al 2004).…”