Time-resolved functional 1H MR spectroscopic detection of glutamate concentration changes in the brain during acute heat pain stimulation
Introduction
Due to its protective function with respect to human survival, perception of pain represents one of the most important physiological senses. However, if acute pain turns to chronic pain its relevance for maintaining health is lost, and quality of life for the affected person may decline dramatically. Chronic pain is furthermore associated with high direct and indirect costs for health care systems due to potential invalidity and lifelong therapy. Therefore, improved understanding of the physiological processes underlying subjective pain perception may help to develop specific preventive or therapeutic methods for managing chronic pain disease (Borsook et al., 2007). The availability and application of modern functional imaging methods like functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) has already revealed new insights into human pain processing (Peyron et al., 2000, Apkarian et al., 2005, Melzack, 2005). However, measuring changes of blood oxygenation level by fMRI or detecting glucose consumption alterations by PET only reflects changes of global neuronal energy uptake related to neuronal activity without a direct link to the underlying metabolic processes. Unlike these techniques, in vivo proton magnetic resonance spectroscopy (1H-MRS) makes it possible to selectively detect specific excitatory or inhibitory neurotransmitters in the brain, such as glutamate (Glu), γ-aminobutyric acid (GABA) or intermediate neurotransmission products, like glutamine (Gln).
Few recently published in vivo 1H-MRS studies reported on local changes of cortical Glu and Gln levels during acute painful stimulation (Mullins et al., 2005) as well as in the presence of chronic pain (Grachev et al., 2002, Siddall et al., 2006, Harris et al., 2008). The results suggest that spectroscopically estimated metabolic levels reflect interactions between excitatory neurotransmitter systems during cortical processing of pain stimuli and may thus allow a more objective evaluation of pain intensities compared to subjectively assessed intensities (Mullins et al., 2005).
Currently, the accuracy of in vivo 1H-MR spectroscopic measurement of Glu, Gln and GABA is limited by their complex spectral multiplet structures and spectral overlapping with further signals of similar chemical shifts. Nevertheless, due to its relatively high concentration in the brain (ca. 8–10 mmol/l), Glu can be reliably quantified by using conventional 1H-MRS localization techniques (PRESS, STEAM) on clinical whole body MR scanners with magnetic fields ≥ 3 T (Schubert et al., 2004, Mullins et al., 2008, Gussew et al., 2008). In contrast, the low cortical levels of Gln (2–4 mmol/l (Govindaraju et al., 2000)) and GABA (1–2 mmol/l (Govindaraju et al., 2000)) require improved detection sensitivity which can, for instance, be realized by using stronger magnetic fields (> 3 T) (Tkáč et al., 2001). Other possibilities include specific MR spectroscopic techniques, like 2D J-resolved 1H-MRS (Lymer et al., 2007), or methods based on spectral editing (Bogner et al., 2008).
Numerous fMRI and PET studies (Casey, 1999, Craig et al., 2000, Baliki et al., 2006) have confirmed that the anterior insular cortex (aIC) is directly involved in the general cortical processing of pain. The goal of this study was to investigate changes of Glu concentrations in the aIC of healthy volunteers, induced by peripheral painful heat stimulation, by acquiring time-resolved, stimulus triggered 1H-MR spectra. In contrast to the study of Mullins et al. (2005), who investigated the alteration of Glu and Gln in the anterior cingulate cortex (ACC) between a resting period and a continuously applied cold pain stimulus (10 min), we chose a cyclic application of short, repetitive heat stimuli. This way we intended to avoid adaptation processes due to nociceptor saturation which may affect metabolic changes during prolonged stimulation (Giove et al., 2003). Furthermore, temporal synchronization between repeated acquisitions and pain stimulation was implemented to acquire the spectra during exactly defined stimulation states.
Section snippets
Volunteers and heat stimulation
Six healthy, right-handed male subjects (mean age 31.1 ± 11.1 years) were recruited within the research group. Prior to the experiments volunteers were informed by a radiologist about all procedures and their possible risks and signed an informed consent. The study was approved by the local Ethics Committee.
Stimulation set-up
Painful heat stimuli were applied to the inner skin area of the left forearm (see Fig. 1a) by using a Peltier element thermode (Neuro Sensory Analyzer TSA-II, MEDOC Ltd., Ramat Yishay,
Results
All spectra showed high SNR and spectral resolution as revealed by the mean SNRNAA of 12.2 ± 2.4 and mean FWHMNAA of 4.6 ± 1.0 Hz (average over all spectra and all volunteers). This is also reflected by low CRLB for the Glu intensities averaged over all spectra and all subjects (CRLBGlu: 10.1 ± 1.5%). The mean tissue fractions of the MRS-voxel were 63.4 ± 2.2% GM, 32.1 ± 3.9% WM and 4.5 ± 2.3% CSF, averaged over all volunteers.
Intra-individual absolute concentrations of Glu, NAA, Cr, total choline and mI
Discussion
Numerous recently published fMRI and PET studies have demonstrated that neuronal activations in the anterior insular cortex (aIC) are strongly associated with cognitive processing of acute pain in the human brain (Casey, 1999, Craig et al., 2000, Brooks et al., 2002). Therefore, the detected changes of the Glu concentration during thermal pain stimulation may reflect a modified glutamatergic neurotransmission in this brain region. Since no evidence of strong lateralization has been reported in
Acknowledgments
The authors thank Prof. Dr. K.-J. Bär for making available the heat stimulus device used for the experiments. This study was supported by the Centre for Interdisciplinary Prevention of Diseases related to Professional Activities (KIP) founded by the Friedrich-Schiller-University Jena and the Accident Prevention and Insurance Association for Food and Restaurants (Berufsgenossenschaft Nahrungsmittel und Gaststätten, BGN, Germany). A.G. acknowledges support from a stipend provided by KIP (project
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