High gamma-aminobutyric acid level in cortical tubers in epileptic infants with tuberous sclerosis complex measured with the MEGA-editing J-difference method and a three-Tesla clinical MRI Instrument
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results in epileptic disease. In patients with TSC, both the number and location of cortical hamartomatous lesions (cortical tubers) are closely related to the mental outcome and influence epileptic symptoms, occasionally causing infantile spasms (Roach et al., 1987, Shepherd et al., 1995). A few proton magnetic resonance spectroscopy (MRS) studies have demonstrated differences in metabolites between cortical tubers and normal-appearing white matter in patients with TSC (Mukonoweshuro et al., 2001) and age-matched normal brains (Mizuno et al., 2000, Matsuo et al., 2006, Yapici et al., 2007). Consistent results observed in these studies were decreased N-acetyl aspartate (NAA)-associated values, such as NAA/creatine plus phosphocreatine (Cr) and increased myo-inositol (mIns)-associated values, such as mIns/Cr in cortical tubers. Yapici et al. (2007) reported increases in choline-containing compounds (Cho)-correlated values such as Cho/Cr, but most other studies found no differences from the control values. Sharma et al. (2005) suggested the utility of proton MRS in elucidating the pathophysiologic function of tubers and in distinguishing benign lesions from gliomas prior to a surgical exploration.
The metabolism of gamma-amino butyric acid (GABA) and glutamate (Glu) in the synthesis of neurotransmitters may correlate with the mechanism of epilepsy. Glutamate is the principal excitatory transmitter and GABA is responsible for most of the inhibitory communication in the brain. However, recent intensive studies have revealed the polarity of action of GABA, that is, the ability of GABA to switch from inhibition to excitation in the developing brain and in epilepsy (Ben-Ari, 2002, Ben-Ari and Holmes, 2005, Ben-Ari et al., 2006, Khazipov et al., 2004). These studies suggest that the activation of GABAergic synapses excites neurons instead of producing classical inhibition, and this shift has major potential consequences for both the operation of networks and the pathogenic effects of epilepsy. This consideration indicates the importance of measuring GABA and Glu concentrations in hamartomatous lesions in patients with TSC to clarify the etiology of the lesions and associated seizure mechanism.
Advances of clinical MR instrumentation and proton MR spectroscopic techniques have made it possible to measure GABA and Glu levels in the brain noninvasively. Because the increase in field strength results not only in an increased signal-to-noise ratio but also an increase in spectrum frequency resolution, a clinical three-Tesla instrument should improve the differentiation of complex peaks and quality of signal editing. To increase the reliability of the signals for GABA in this study, MEGA was incorporated into a point-resolved spectroscopic sequence (PRESS) in a three-Tesla instrument to obtain J-difference spectra introduced by Mescher et al. (1998). The obtained spectra were analyzed by LCModel (Provencher, 1993) using the original basis-set for the MEGA-editing method (MEGA-PRESS). Because a large difference in the GABA concentration has been demonstrated between the gray matter (GM) and the white matter (WM) (Petroff et al., 1988), segmentation of the cerebrospinal fluid (CSF), GM and WM was conducted in healthy subjects and in the normal-appearing parenchyma in patients with TSC, and GABA levels in the GM and WM were calculated on the basis of previously reported GABA concentration ratios in the GM and WM.
Glutamine plus glutamate complex (Glx) and myo-inositol (mIns) can be detected with a short echo time (TE) more so dominantly than a long TE (Constantinidis, 2000; Simister et al., 2003). Because the quantitation of Glx is usually conducted using a short TE sequence (Constantinidis, 2000), a conventional stimulated echo-acquisition mode (STEAM) sequence with a short TE was applied and used to quantify major metabolites including Glx and mIns. Concentrations of GABA were measured by MEGA-PRESS with a similar procedure using two different sequences, according to Simister et al. (2003).
The purpose of this study was to estimate the GABA and Glu levels in the cortical tubers of patients with TS using the MEGA-PRESS and a conventional STEAM sequence with short TE, and to determine which abnormality was more dominant between GABA and Glu in patients with TSC with epilepsy.
Section snippets
Subjects and methods
Subjects included six patients (2 boys and 4 girls; mean age, 4.3 years; range, 3–7 years) who met the criteria for a definite diagnosis of TSC, which was established by means of identification of either multiple cortical tubers or multiple subependymal nodules in addition to another major feature (facial angiofibroma, forehead plaque, or several hypomelanotic macules), and seven age-matched healthy control subjects (3 boys and 4 girls; mean age, 4.8 years; range, 3–8 years). Control subjects
Result
The volume ratios (%) for CSF, GM and WM in voxels by segmentation were 4.5 ± 1.7, 58.3 ± 2.1 and 37.3 ± 3.2, respectively. The distribution of the volume ratios according to age is shown in Fig. 3. There was no remarkable difference in ratios in each component according to age. The typical spectrum of a conventional STEAM sequence in a control subject and a patient with TSC are shown in Figs. 4a and b, and that of a MEGA-PRESS in a control subject and a patient are shown in Figs. 5a and b. The GABA
Discussion
It is well known that GABA is an inhibitory neurotransmitter that acts on a receptor channel complex permeable mainly to chloride anions, which act to reduce neuronal excitability in the developed brain. Therefore, GABAergic signaling plays a major role in the brain physiology, and a dysfunction of GABAergic signaling can result in pathologic conditions, such as epilepsy, which occurs when the balance between excitation and inhibition is impaired. Recent studies have revealed that GABA
References (33)
- et al.
Proton magnetic resonance spectroscopy of brain biopsies from patients with intractable epilepsy
Epilepsy Res.
(1999) - et al.
In vivo detection of gray and white matter differences in GABA concentration in the human brain
NeuroImage
(2006) - et al.
Solvent suppression using selective echo dephasing
J. Magn. Reson. Series A
(1996) - et al.
Effect of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures
Seizure
(1999) - et al.
Proton magnetic resonance spectroscopy of malformations of cortical development causing epilepsy
Epilepsy Res.
(2007) - et al.
Effects of vigabatrin intake on brain GABA activity as monitored by spectrally edited magnetic resonance spectroscopy and positron emission tomography
Magn. Reson. Imaging
(1999) Excitatory actions of GABA during development: the nature of the nurture
Nat. Rev. Neurosci.
(2002)- et al.
The multiple facets of γ-aminobutyric acid dysfunction in epilepsy
Curr. Opin. Neurol.
(2005) - et al.
GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations
Physiol. Rev.
(2006) - et al.
Measurement of GABA and contaminants in gray and white matter in human brain in vivo
Magn. Reson. Med.
(2007)
Localized proton MRS of the human hippocampus metabolites concentrations and relaxation times
Magn. Reson. Med.
MRS methodology
Adv. Neurol.
Neuronal impairment of adult moyamoya disease detected by quantified proton MRS and comparison with cerebral perfusion by SPECT with Tc-99m HM-PAO: a trial of clinical quantification of metabolites
J. Magn. Reson. Imaging
Developmental brain changes investigated with proton magnetic resonance spectroscopy
Dev. Med. Child Neurol.
Gray and white matter GABA level differences in the human brain using two-dimensional, J-resolved spectroscopic imaging
NMR Biomed.
Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus
Eur. J. Neruosci.
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